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Biophysical approach reveals a novel allosteric ligand binding site of SMYD3 histone methyltransferase
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Department of Pharmacy and Biotechnology, University of Bologna.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

SET-and MYND-domain containing protein 3 (SMYD3) is a lysine methyltransferase that plays a role in epigenetic regulation. The protein was shown to have cancerogenic activities and is considered to be a perspective drug target. Here, we propose a Surface Plasmon Resonance-based (SPR) biophysical platform to aid SMYD3 drug discovery. The SPR screening assay was validated with a small subset of drug-like compounds, and resulted in an assay hit. The hit compound-SMYD3 complex structure was solved, and a new allosteric ligand binding site of the protein was revealed. The interaction was found localized within the previously reported SMYD3-heat shock protein 90 (HSP90) recognition site, thereby rendering the hit compound as a perspective candidate for a development of a protein-protein interface inhibitor.

National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry; Medicinal Chemistry; Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-363297OAI: oai:DiVA.org:uu-363297DiVA, id: diva2:1256237
Available from: 2018-10-16 Created: 2018-10-16 Last updated: 2018-10-16
In thesis
1. Interaction kinetic analysis in drug design, enzymology and protein research
Open this publication in new window or tab >>Interaction kinetic analysis in drug design, enzymology and protein research
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work presented here is focused on the phenomenon of molecular recognition – the mutual ability of biological molecules to recognize each other through their chemical signatures. Here, the kinetic aspects of recognition were evaluated, as interaction kinetics reveal valuable dimensions in the description of molecular events in biological systems. The primary objects studied in this thesis were human proteins and their interaction partners. Proteins serve a fundamental role in living organisms, supporting the biochemical machinery by means of catalysis, signalling and transport; additionally, proteins are the main targets for drugs.

In the first study, carbonic anhydrase (CA) isozymes were employed as a model system to address the problem of drug selectivity. Kinetic signatures preferable for the design of selective sulphonamide-based inhibitors were identified. In a follow up study, the recognition between CA and sulphonamides was separated into two parts, uncovering intrinsic recognition features that genuinely reflect the interaction mechanism. For the first time, the concept of intrinsic interaction kinetics was applied to a drug-target system.

Another model protein studied in this thesis was calmodulin (CaM), as its interactions with other proteins should have specific kinetic signatures to support the dynamics of calcium-dependent signalling. The study evolved around calcium-dependent CaM interactions with the neuronal protein neurogranin (Ng), and revealed its complex nature. Ng was found to interact with CaM both in presence and absence of calcium, but with different kinetics and affinity. This finding supports development of a mechanistic model of calcium sensitivity regulation.

The last two projects were more applied, exploring the druggability of an emerging class of pharmaceutical targets – epigenetic enzymes. Expertise and methodology for biophysically guided drug discovery towards histone demethylase LSD1 and histone methyltransferase SMYD3 were developed. For LSD1, the project assisted the rational design of active site-targeting macrocyclic peptides, and resulted in the development of competitive inhibitors with a well described mechanism of action. A novel biophysical platform for screening was developed for SMYD3. It proved to be successful, as it identified previously unknown allosteric ligand binding site. Both projects were supported by structural studies, expanding the druggable space of epigenetic targets.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 51
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1735
National Category
Biochemistry and Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-363323 (URN)978-91-513-0479-3 (ISBN)
Public defence
2018-12-05, B42, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2018-11-09 Created: 2018-10-16 Last updated: 2018-11-09

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