Ändra sökning
Avgränsa sökresultatet
1 - 21 av 21
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Träffar per sida
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
Markera
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 1. Aebersold, Ruedi
    et al.
    Agar, Jeffrey N.
    Amster, I. Jonathan
    Baker, Mark S.
    Bertozzi, Carolyn R.
    Boja, Emily S.
    Costello, Catherine E.
    Cravatt, Benjamin F.
    Fenselau, Catherine
    Garcia, Benjamin A.
    Ge, Ying
    Gunawardena, Jeremy
    Hendrickson, Ronald C.
    Hergenrother, Paul J.
    Huber, Christian G.
    Ivanov, Alexander R.
    Jensen, Ole N.
    Jewett, Michael C.
    Kelleher, Neil L.
    Kiessling, Laura L.
    Krogan, Nevan J.
    Larsen, Martin R.
    Loo, Joseph A.
    Loo, Rachel R. Ogorzalek
    Lundberg, Emma
    KTH, Centra, Science for Life Laboratory, SciLifeLab. Stanford Univ, Dept Genet, Stanford, CA 94305 USA.
    MacCoss, Michael J.
    Mallick, Parag
    Mootha, Vamsi K.
    Mrksich, Milan
    Muir, Tom W.
    Patrie, Steven M.
    Pesavento, James J.
    Pitteri, Sharon J.
    Rodriguez, Henry
    Saghatelian, Alan
    Sandoval, Wendy
    Schluter, Hartmut
    Sechi, Salvatore
    Slavoff, Sarah A.
    Smith, Lloyd M.
    Snyder, Michael P.
    Thomas, Paul M.
    Uhlen, Mathias
    Van Eyk, Jennifer E.
    Vidal, Marc
    Walt, David R.
    White, Forest M.
    Williams, Evan R.
    Wohlschlager, Therese
    Wysocki, Vicki H.
    Yates, Nathan A.
    Young, Nicolas L.
    Zhang, Bing
    How many human proteoforms are there?2018Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, nr 3, s. 206-214Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA-and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.

  • 2. Andersson, Marlene
    et al.
    Jia, Qiupin
    Abella, Ana
    Lee, Xiau-Yeen
    Landreh, Michael
    Purhonen, Pasi
    KTH, Skolan för teknik och hälsa (STH).
    Hebert, Hans
    KTH, Skolan för teknik och hälsa (STH), Naturvetenskap och biomedicin, Strukturell bioteknik.
    Tenje, Maria
    Robinson, Carol V.
    Meng, Qing
    Plaza, Gustavo R.
    Johansson, Jan
    Rising, Anna
    Biomimetic spinning of artificial spider silk from a chimeric minispidroin2017Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, nr 3, s. 262-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein we present a chimeric recombinant spider silk protein (spidroin) whose aqueous solubility equals that of native spider silk dope and a spinning device that is based solely on aqueous buffers, shear forces and lowered pH. The process recapitulates the complex molecular mechanisms that dictate native spider silk spinning and is highly efficient; spidroin from one liter of bacterial shake-flask culture is enough to spin a kilometer of the hitherto toughest as-spun artificial spider silk fiber.

  • 3.
    Andersson, Marlene
    et al.
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Jia, Qiupin
    Institute of Biological Sciences and Biotechnology, Donghua University, Shanghai, P.R. China..
    Abella, Ana
    ETSI de Caminos and Center for Biomedical Technology, Universidad Politécnica de Madrid, Madrid, Spain..
    Lee, Xiau-Yeen
    ETSI de Caminos and Center for Biomedical Technology, Universidad Politécnica de Madrid, Madrid, Spain..
    Landreh, Michael
    Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK..
    Purhonen, Pasi
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; School of Technology and Health, KTH Royal Institute of Technology, Stockholm, Sweden..
    Hebert, Hans
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; School of Technology and Health, KTH Royal Institute of Technology, Stockholm, Sweden..
    Tenje, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Biomedical Engineering, Lund University, Lund, Sweden..
    Robinson, Carol V.
    Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, Oxford, UK..
    Meng, Qing
    Institute of Biological Sciences and Biotechnology, Donghua University, Shanghai, P.R. China..
    Plaza, Gustavo R.
    ETSI de Caminos and Center for Biomedical Technology, Universidad Politécnica de Madrid, Madrid, Spain..
    Johansson, Jan
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.; Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden.; Karolinska Institutet.
    Rising, Anna
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.;Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Stockholm, Sweden.; Karolinska Institutet.
    Biomimetic spinning of artificial spider silk from a chimeric minispidroin2017Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, nr 3, s. 262-264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein we present a chimeric recombinant spider silk protein (spidroin) whose aqueous solubility equals that of native spider silk dope and a spinning device that is based solely on aqueous buffers, shear forces and lowered pH. The process recapitulates the complex molecular mechanisms that dictate native spider silk spinning and is highly efficient; spidroin from one liter of bacterial shake-flask culture is enough to spin a kilometer of the hitherto toughest as-spun artificial spider silk fiber.

  • 4. Esselborn, Julian
    et al.
    Lambertz, Camilla
    Adamska-Venkatesh, Agnieszka
    Simmons, Trevor
    Berggren, Gustav
    Noth, Jens
    Siebel, Judith
    Hemschemeier, Anja
    Artero, Vincent
    Reijerse, Edward
    Fontecave, Marc
    Lubitz, Wolfgang
    Happe, Thomas
    Spontaneous activation of [FeFe]-hydrogenases by an inorganic [2Fe] active site mimic2013Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 9, nr 10, s. 607-609Artikel i tidskrift (Refereegranskat)
  • 5. Esselborn, Julian
    et al.
    Lambertz, Camilla
    Adamska-Venkatesh, Agnieszka
    Simmons, Trevor
    Berggren, Gustav
    Laboratoire de Chimie et Biologie des Métaux (Commissariat à l'énergie atomique et aux énergies alternatives–Université Grenoble 1–Centre national de la recherche scientifique), Grenoble, France..
    Nothl, Jens
    Siebel, Judith
    Hemschemeier, Anja
    Artero, Vincent
    Reijerse, Edward
    Fontecave, Marc
    Lubitz, Wolfgang
    Happe, Thomas
    Spontaneous activation of [FeFe]-hydrogenases by an inorganic [2Fe] active site mimic2013Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 9, nr 10, s. 607-609Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Hydrogenases catalyze the formation of hydrogen. The cofactor ('H-cluster') of [FeFe]-hydrogenases consists of a [4Fe-4S] cluster bridged to a unique [2Fe] subcluster whose biosynthesis in vivo requires hydrogenase-specific maturases. Here we show that a chemical mimic of the [2Fe] subcluster can reconstitute apo-hydrogenase to full activity, independent of helper proteins. The assembled H-cluster is virtually indistinguishable from the native cofactor. This procedure will be a powerful tool for developing new artificial H-2-producing catalysts.

  • 6. Hindie, Valerie
    et al.
    Stroba, Adriana
    Zhang, Hua
    Lopez-Garcia, Laura A
    Idrissova, Leila
    Zeuzem, Stefan
    Hirschberg, Daniel
    Schaeffer, Francis
    Jørgensen, Thomas J D
    Engel, Matthias
    Alzari, Pedro M
    Biondi, Ricardo M
    Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1.2009Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 5, nr 10Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein phosphorylation transduces a large set of intracellular signals. One mechanism by which phosphorylation mediates signal transduction is by prompting conformational changes in the target protein or interacting proteins. Previous work described an allosteric site mediating phosphorylation-dependent activation of AGC kinases. The AGC kinase PDK1 is activated by the docking of a phosphorylated motif from substrates. Here we present the crystallography of PDK1 bound to a rationally developed low-molecular-weight activator and describe the conformational changes induced by small compounds in the crystal and in solution using a fluorescence-based assay and deuterium exchange experiments. Our results indicate that the binding of the compound produces local changes at the target site, the PIF binding pocket, and also allosteric changes at the ATP binding site and the activation loop. Altogether, we present molecular details of the allosteric changes induced by small compounds that trigger the activation of PDK1 through mimicry of phosphorylation-dependent conformational changes.

  • 7. Jansson, Emmelie Å
    et al.
    Huang, Liyue
    Malkey, Ronny
    Govoni, Mirco
    Nihlén, Carina
    Olsson, Annika
    Stensdotter, Margareta
    Petersson, Joel
    Holm, Lena
    Department of Physiology and Pharmacology, Division of Anesthesiology and Intensive Care, Karolinska Institutet.
    Weitzberg, Eddie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lundberg, Jon O
    A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis2008Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 4, nr 7, s. 411-417Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.

  • 8.
    Kaltenbach, Miriam
    et al.
    Weizmann Inst Sci, Dept Biol Chem, Rehovot, Israel.
    Burke, Jason R.
    Salk Inst Biol Studies, Howard Hughes Med Inst, Jack H Skirball Ctr Chem Biol & Prote, La Jolla, CA 92037 USA.
    Dindo, Mirco
    Weizmann Inst Sci, Dept Biol Chem, Rehovot, Israel;Univ Verona, Biol Chem Sect, Dept Neurosci Biomed & Movement Sci, Verona, Italy.
    Pabis, Anna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär biofysik.
    Steffen-Munsberg, Fabian
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Rabin, Avigayel
    Weizmann Inst Sci, Dept Biol Chem, Rehovot, Israel;Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, Edmond J Safra Campus, Jerusalem, Israel.
    Kamerlin, Shina C. Lynn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Strukturbiologi.
    Noel, Joseph P.
    Salk Inst Biol Studies, Howard Hughes Med Inst, Jack H Skirball Ctr Chem Biol & Prote, La Jolla, CA 92037 USA.
    Tawfik, Dan S.
    Weizmann Inst Sci, Dept Biol Chem, Rehovot, Israel.
    Evolution of chalcone isomerase from a noncatalytic ancestor2018Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, nr 6, s. 548-555Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The emergence of catalysis in a noncatalytic protein scaffold is a rare, unexplored event. Chalcone isomerase (CHI), a key enzyme in plant flavonoid biosynthesis, is presumed to have evolved from a nonenzymatic ancestor related to the widely distributed fatty-acid binding proteins (FAPs) and a plant protein family with no isomerase activity (CHILs). Ancestral inference supported the evolution of CHI from a protein lacking isomerase activity. Further, we identified four alternative founder mutations, i.e., mutations that individually instated activity, including a mutation that is not phylogenetically traceable. Despite strong epistasis in other cases of protein evolution, CHI's laboratory reconstructed mutational trajectory shows weak epistasis. Thus, enantioselective CHI activity could readily emerge despite a catalytically inactive starting point. Accordingly, X-ray crystallography, NMR, and molecular dynamics simulations reveal reshaping of the active site toward a productive substratebinding mode and repositioning of the catalytic arginine that was inherited from the ancestral fatty-acid binding proteins.

  • 9.
    Licciardello, Marco P.
    et al.
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Inst Canc Res, Canc Res UK Canc Therapeut Unit, London, England..
    Ringler, Anna
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
    Markt, Patrick
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Univ Innsbruck Hosp, Dept Pharm, Innsbruck, Austria..
    Klepsch, Freya
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Chem Comp Grp Inc, Cologne, Germany..
    Lardeau, Charles-Hugues
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Austrian Acad Sci, CeMM Res Ctr Mol Med, Christian Doppler Lab Chem Epigenet & Anti Infect, Vienna, Austria..
    Sdelci, Sara
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
    Schirghuber, Erika
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Austrian Acad Sci, CeMM Res Ctr Mol Med, Christian Doppler Lab Chem Epigenet & Anti Infect, Vienna, Austria..
    Mueller, Andre C.
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
    Caldera, Michael
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
    Wagner, Anja
    Med Univ Vienna, Dept Pediat & Adolescent Med, Christian Doppler Lab Mol Stress Res Peritoneal D, Vienna, Austria..
    Herzog, Rebecca
    Med Univ Vienna, Dept Pediat & Adolescent Med, Christian Doppler Lab Mol Stress Res Peritoneal D, Vienna, Austria..
    Penz, Thomas
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
    Schuster, Michael
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
    Boidol, Bernd
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Austrian Acad Sci, CeMM Res Ctr Mol Med, Christian Doppler Lab Chem Epigenet & Anti Infect, Vienna, Austria..
    Duernberger, Gerhard
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Gregor Mendel Inst, Vienna, Austria..
    Folkvaljon, Yasin
    Umea Univ Hosp, Dept Surg & Perioperat Sci, Urol & Androl, Umea, Sweden..
    Stattin, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi. Umea Univ Hosp, Dept Surg & Perioperat Sci, Urol & Androl, Umea, Sweden.
    Ivanov, Vladimir
    Enamine Ltd, Kiev, Ukraine..
    Colinge, Jacques
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Univ Montpellier, Fac Med, Montpellier, France.;Inst Reg Canc Montpellier, INSERM U1194, Inst Rech Cancerol Montpellier, Montpellier, France..
    Bock, Christoph
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Med Univ Vienna, Dept Lab Med, Vienna, Austria.;Max Planck Inst Informat, Saarland Informat Campus, Saarbrucken, Germany..
    Kratochwill, Klaus
    Med Univ Vienna, Dept Pediat & Adolescent Med, Christian Doppler Lab Mol Stress Res Peritoneal D, Vienna, Austria..
    Menche, Joerg
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
    Bennett, Keiryn L.
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria..
    Kubicek, Stefan
    Austrian Acad Sci, CeMM Res Ctr Mol Med, Vienna, Austria.;Austrian Acad Sci, CeMM Res Ctr Mol Med, Christian Doppler Lab Chem Epigenet & Anti Infect, Vienna, Austria..
    A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor2017Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, nr 7, s. 771-778Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for gamma-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.

  • 10. Licciardello, Marco P.
    et al.
    Ringler, Anna
    Markt, Patrick
    Klepsch, Freya
    Lardeau, Charles-Hugues
    Sdelci, Sara
    Schirghuber, Erika
    Mueller, Andre C.
    Caldera, Michael
    Wagner, Anja
    Herzog, Rebecca
    Penz, Thomas
    Schuster, Michael
    Boidol, Bernd
    Duernberger, Gerhard
    Folkvaljon, Yasin
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
    Ivanov, Vladimir
    Colinge, Jacques
    Bock, Christoph
    Kratochwill, Klaus
    Menche, Joerg
    Bennett, Keiryn L.
    Kubicek, Stefan
    A combinatorial screen of the CLOUD uncovers a synergy targeting the androgen receptor2017Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, nr 7, s. 771-778Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Approved drugs are invaluable tools to study biochemical pathways, and further characterization of these compounds may lead to repurposing of single drugs or combinations. Here we describe a collection of 308 small molecules representing the diversity of structures and molecular targets of all FDA-approved chemical entities. The CeMM Library of Unique Drugs (CLOUD) covers prodrugs and active forms at pharmacologically relevant concentrations and is ideally suited for combinatorial studies. We screened pairwise combinations of CLOUD drugs for impairment of cancer cell viability and discovered a synergistic interaction between flutamide and phenprocoumon (PPC). The combination of these drugs modulates the stability of the androgen receptor (AR) and resensitizes AR-mutant prostate cancer cells to flutamide. Mechanistically, we show that the AR is a substrate for gamma-carboxylation, a post-translational modification inhibited by PPC. Collectively, our data suggest that PPC could be repurposed to tackle resistance to antiandrogens in prostate cancer patients.

  • 11. Lindén, Martin
    Pulling out the coordination mechanism of myosin-VI2009Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 5, nr 6, s. 376-377Artikel i tidskrift (Övrigt vetenskapligt)
  • 12.
    Lundgren, Camilla A. K.
    et al.
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    Sjostrand, Dan
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    Biner, Olivier
    Univ Bern, Dept Chem & Biochem, Bern, Switzerland.
    Bennett, Matthew
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    Rudling, Axel
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Johansson, Ann-Louise
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    Brzezinski, Peter
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    Carlsson, Jens
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    von Ballmoos, Christoph
    Univ Bern, Dept Chem & Biochem, Bern, Switzerland.
    Högbom, Martin
    Stockholm Univ, Dept Biochem & Biophys, Stockholm, Sweden.
    Scavenging of superoxide by a membrane-bound superoxide oxidase2018Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, nr 8, s. 788-793Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Superoxide is a reactive oxygen species produced during aerobic metabolism in mitochondria and prokaryotes. It causes damage to lipids, proteins and DNA and is implicated in cancer, cardiovascular disease, neurodegenerative disorders and aging. As protection, cells express soluble superoxide dismutases, disproportionating superoxide to oxygen and hydrogen peroxide. Here, we describe a membrane-bound enzyme that directly oxidizes superoxide and funnels the sequestered electrons to ubiquinone in a diffusion-limited reaction. Experiments in proteoliposomes and inverted membranes show that the protein is capable of efficiently quenching superoxide generated at the membrane in vitro. The 2.0 angstrom crystal structure shows an integral membrane di-heme cytochrome b poised for electron transfer from the P-side and proton uptake from the N-side. This suggests that the reaction is electrogenic and contributes to the membrane potential while also conserving energy by reducing the quinone pool. Based on this enzymatic activity, we propose that the enzyme family be denoted superoxide oxidase (SOO).

  • 13.
    Lundgren, Camilla A. K
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Sjöstrand, Dan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Biner, Olivier
    Bennett, Matthew
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Rudling, Axel
    Johansson, Ann-Louise
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Brzezinsk, Peter
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Carlsson, Jens
    von Ballmoos, Christoph
    Högbom, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Scavenging of superoxide by a membrane-bound superoxide oxidase2018Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, s. 788-793Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Superoxide is a reactive oxygen species produced during aerobic metabolism in mitochondria and prokaryotes. It causes damage to lipids, proteins and DNA and is implicated in cancer, cardiovascular disease, neurodegenerative disorders and aging. As protection, cells express soluble superoxide dismutases, disproportionating superoxide to oxygen and hydrogen peroxide. Here, we describe a membrane-bound enzyme that directly oxidizes superoxide and funnels the sequestered electrons to ubiquinone in a diffusion-limited reaction. Experiments in proteoliposomes and inverted membranes show that the protein is capable of efficiently quenching superoxide generated at the membrane in vitro. The 2.0 Å crystal structure shows an integral membrane di-heme cytochrome b poised for electron transfer from the P-side and proton uptake from the N-side. This suggests that the reaction is electrogenic and contributes to the membrane potential while also conserving energy by reducing the quinone pool. Based on this enzymatic activity, we propose that the enzyme family be denoted superoxide oxidase (SOO).

  • 14. Nick McElhinny, Stephanie A
    et al.
    Kumar, Dinesh
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Clark, Alan B
    Watt, Danielle L
    Watts, Brian E
    Lundström, Else-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Johansson, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chabes, Andrei
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kunkel, Thomas A
    Genome instability due to ribonucleotide incorporation into DNA2010Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 6, nr 10, s. 774-81Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Maintaining the chemical identity of DNA depends on ribonucleotide exclusion by DNA polymerases. However, ribonucleotide exclusion during DNA synthesis in vitro is imperfect. To determine whether ribonucleotides are incorporated during DNA replication in vivo, we substituted leucine or glycine for an active-site methionine in yeast DNA polymerase ϵ (Pol ϵ). Ribonucleotide incorporation in vitro was three-fold lower for M644L and 11-fold higher for M644G Pol ϵ compared to wild-type Pol ϵ. This hierarchy was recapitulated in vivo in yeast strains lacking RNase H2. Moreover, the pol2-M644G rnh201Δ strain progressed more slowly through S phase, had elevated dNTP pools and generated 2-5-base-pair deletions in repetitive sequences at a high rate and in a gene orientation-dependent manner. The data indicate that ribonucleotides are incorporated during replication in vivo, that they are removed by RNase H2-dependent repair and that defective repair results in replicative stress and genome instability via DNA strand misalignment.

  • 15.
    Nielsen, Jens
    et al.
    KTH, Skolan för bioteknologi (BIO), Genteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    Fussenegger, Martin
    Keasling, Jay
    Lee, Sang Yup
    Liao, James C.
    Prather, Kristala
    Palsson, Bernhard
    Engineering synergy in biotechnology2014Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 10, nr 5, s. 319-322Artikel i tidskrift (Refereegranskat)
  • 16. Nim, Satra
    et al.
    Jeon, Jouhyun
    Corbi-Verge, Carles
    Seo, Moon-Hyeong
    Ivarsson, Ylva
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Moffat, Jason
    Tarasova, Nadya
    Kim, Philip M
    Pooled screening for antiproliferative inhibitors of protein-protein interactions.2016Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, nr 4, s. 275-281Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein-protein interactions (PPIs) are emerging as a promising new class of drug targets. Here, we present a novel high-throughput approach to screen inhibitors of PPIs in cells. We designed a library of 50,000 human peptide-binding motifs and used a pooled lentiviral system to express them intracellularly and screen for their effects on cell proliferation. We thereby identified inhibitors that drastically reduced the viability of a pancreatic cancer line (RWP1) while leaving a control line virtually unaffected. We identified their target interactions computationally, and validated a subset in experiments. We also discovered their potential mechanisms of action, including apoptosis and cell cycle arrest. Finally, we confirmed that synthetic lipopeptide versions of our inhibitors have similarly specific and dosage-dependent effects on cancer cell growth. Our screen reveals new drug targets and peptide drug leads, and it provides a rich data set covering phenotypes for the inhibition of thousands of interactions.

  • 17.
    Over, Bjorn
    et al.
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Molndal, Sweden..
    Matsson, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tyrchan, Christian
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Doak, Bradley C.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Fysikalisk-organisk kemi.
    Foley, Michael A.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Triinst Therapeut Discovery Inst, New York, NY USA..
    Hilgendorf, Constanze
    AstraZeneca R&D Gothenburg, Safety & ADME Translat Sci, Drug Safety & Metab, Molndal, Sweden..
    Johnston, Stephen E.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA..
    Lee, Maurice D.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Lewis, Richard J.
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
    McCarren, Patrick
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA..
    Muncipinto, Giovanni
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Norinder, Ulf
    Swedish Toxicol Sci Res Ctr, Sodertalje, Sweden..
    Perry, Matthew W. D.
    Duvall, Jeremy R.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Kihlberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Structural and conformational determinants of macrocycle cell permeability2016Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, nr 12, s. 1065-+Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 nonpeptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

  • 18. Patton, Gregory C.
    et al.
    Stenmark, Pål
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Gollapalli, Deviprasad R.
    Sevastik, Robin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Kursula, Petri
    Flodin, Susanne
    Schuler, Herwig
    Swales, Colin T.
    Eklund, Hans
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Nordlund, Par
    Hedstrom, Lizbeth
    Cofactor mobility determines reaction outcome in the IMPDH and GMPR (beta-alpha)(8) barrel enzymes2011Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 7, nr 12, s. 950-958Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inosine monophosphate dehydrogenase (IMPDH) and guanosine monophosphate reductase (GMPR) belong to the same structural family, share a common set of catalytic residues and bind the same ligands. The structural and mechanistic features that determine reaction outcome in the IMPDH and GMPR family have not been identified. Here we show that the GMPR reaction uses the same intermediate E-XMP(star) as IMPDH, but in this reaction the intermediate reacts with ammonia instead of water. A single crystal structure of human GMPR type 2 with IMP and NADPH fortuitously captures three different states, each of which mimics a distinct step in the catalytic cycle of GMPR. The cofactor is found in two conformations: an 'in' conformation poised for hydride transfer and an 'out' conformation in which the cofactor is 6 angstrom from IMP. Mutagenesis along with substrate and cofactor analog experiments demonstrate that the out conformation is required for the deamination of GMP. Remarkably, the cofactor is part of the catalytic machinery that activates ammonia.

  • 19.
    Teixeira, Pedro F.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Kmiec, Beata
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Branca, Rui M. M.
    Murcha, Monika W.
    Byzia, Anna
    Ivanova, Aneta
    Whelan, James
    Drag, Marcin
    Lehtio, Janne
    Glaser, Elzbieta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    A multi-step peptidolytic cascade for amino acid recovery in chloroplasts2017Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, nr 1, s. 15-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Plastids (including chloroplasts) are subcellular sites for a plethora of proteolytic reactions, required in functions ranging from protein biogenesis to quality control. Here we show that peptides generated from pre-protein maturation within chloroplasts of Arabidopsis thaliana are degraded to amino acids by a multi-step peptidolytic cascade consisting of oligopeptidases and aminopeptidases, effectively allowing the recovery of single amino acids within these organelles.

  • 20.
    Volkov, Ivan
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Lindén, Martin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Aguirre, Javier
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Ieong, Ka-Weng
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylärbiologi.
    Metelev, Mikhail
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Elf, Johan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    Johansson, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär systembiologi.
    tRNA tracking for direct measurements of protein synthesis kinetics in live cells2018Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 14, nr 6, s. 618-626Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our ability to directly relate results from test-tube biochemical experiments to the kinetics in living cells is very limited. Here we present experimental and analytical tools to directly study the kinetics of fast biochemical reactions in live cells. Dye-labeled molecules are electroporated into bacterial cells and tracked using super-resolved single-molecule microscopy.Trajectories are analyzed by machine-learning algorithms to directly monitor transitions between bound and free states. In particular, we measure the dwell time of tRNAs on ribosomes, and hence achieve direct measurements of translation rates inside living cells at codon resolution. We find elongation rates with tRNA(Phe) that are in perfect agreement with previous indirect estimates, and once fMet-tRNA(fMet) has bound to the 30S ribosomal subunit, initiation of translation is surprisingly fast and does not limit the overall rate of protein synthesis. The experimental and analytical tools for direct kinetics measurements in live cells have applications far beyond bacterial protein synthesis.

  • 21. Zhu, Zhiwei
    et al.
    Zhou, Yongjin J.
    Krivoruchko, Anastasia
    Grininger, Martin
    Zhao, Zongbao K.
    Nielsen, Jens
    Expanding the product portfolio of fungal type I fatty acid synthases2017Ingår i: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 13, nr 4, s. 360-362Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fungal type I fatty acid synthases (FASs) are mega-enzymes with two separated, identical compartments, in which the acyl carrier protein (ACP) domains shuttle substrates to catalytically active sites embedded in the chamber wall. We devised synthetic FASs by integrating heterologous enzymes into the reaction chambers and demonstrated their capability to convert acyl-ACP or acyl-CoA from canonical fatty acid biosynthesis to short/ medium-chain fatty acids and methyl ketones.

1 - 21 av 21
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf