Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Computational Modeling Explains the Multi Sterol Ligand Specificity of the N-Terminal Domain of Niemann-Pick C1-Like 1 Protein
Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.ORCID iD: 0000-0002-8880-9247
Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.ORCID iD: 0000-0002-7725-2164
Univ Southern Denmark, Dept Biochem & Mol Biol, DK-5230 Odense M, Denmark.
2019 (English)In: ACS OMEGA, ISSN 2470-1343, Vol. 4, no 25, p. 20894-20904Article in journal (Refereed) Published
Abstract [en]

Niemann-Pick C1 like 1 (NPC1L1) is a sterol transporter expressed in the apical membrane of enterocytes and hepatocytes. NPC1L1 resembles the lysosomal NPC1 protein including an N-terminal domain (NTD), which binds a variety of sterols. The molecular mechanisms underlying this multiligand specificity of the NTD of NPC1L1 (NPC1L1-NTD) are not known. On the basis of the crystal structure of NPC1L1-NTD, we have investigated the structural details of protein-sterol interactions using molecular mechanics Poisson Boltzmann surface area calculations here. We found a good agreement between experimental and calculated binding affinities with similar ranking of various sterol ligands. We defined hydrogen bonding of sterol ligands via the 3'-beta-hydroxy group inside the binding pose as instrumental in stabilizing the interaction. A leucine residue (LEU213) at the mouth of the binding pocket transiently opens to allow for the access of sterol into the binding pose. Our calculations also predict that NPC1L1-NTD binds polyene sterols, such as dehydroergosterol or cholestatrienol with high affinity, which validates their use in future experiments as close intrinsically fluorescent cholesterol analogs. A free energy decomposition and computational mutation analysis revealed that the binding of various sterols to NPC1L1-NTD depends critically on specific amino acid residues within the binding pocket. Some of these residues were previously detected as being relevant for intestinal cholesterol absorption. We show that clinically known mutations in the NPC1L1-NTD associated with lowered risk of coronary heart disease result in strongly reduced binding energies, providing a molecular explanation for the clinical phenotype.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019. Vol. 4, no 25, p. 20894-20904
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-402387DOI: 10.1021/acsomega.9b01668ISI: 000503370500004PubMedID: 31867479OAI: oai:DiVA.org:uu-402387DiVA, id: diva2:1388724
Available from: 2020-01-27 Created: 2020-01-27 Last updated: 2020-01-27Bibliographically approved

Open Access in DiVA

fulltext(4005 kB)16 downloads
File information
File name FULLTEXT01.pdfFile size 4005 kBChecksum SHA-512
b5d5de247bdd498d21057e1b0af3339d609069f9e197832bc30ce4df2cde48c5c4feffdbe028aa8735d1a41c97ebcadfaf6320fb5fcda50d3778812645616f44
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Poongavanam, VasanthanathanKongsted, Jacob
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 16 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 16 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf