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Discovery of an all...
Discovery of an allosteric ligand binding site in SMYD3 lysine methyltransferase
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- Talibov, Vladimir O, 1991- (author)
- Uppsala universitet,Biokemi
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- Fabini, Edoardo (author)
- Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Via Belmeloro 6, I-40126 Bologna, Italy; CNR, Inst Organ Synth & Photoreact, Via P Gobetti 101, I-40129 Bologna, Italy
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- FitzGerald, Edward (author)
- Uppsala universitet,Biokemi,Beact Therapeut AB, Virdings Alle 2, S-75450 Uppsala, Sweden
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- Tedesco, Daniele (author)
- Alma Mater Studiorum Univ Bologna, Dept Pharm & Biotechnol, Via Belmeloro 6, I-40126 Bologna, Italy; CNR, Inst Organ Synth & Photoreact, Via P Gobetti 101, I-40129 Bologna, Italy
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- Cederfelt, Daniela (author)
- Uppsala universitet,Biokemi
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- Talu, Martin J (author)
- Uppsala universitet,Biokemi
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- Rachman, Moira M (author)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB) and Facultat de Farmacia, Universitat de Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain
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- Mihalic, Filip (author)
- Uppsala universitet,Biokemi
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- Manoni, Elisabetta (author)
- Institute for Organic Synthesis and Photoreactivity, National Research Council, Via P. Gobetti 101, 40129 Bologna, Italy
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- Naldi, Marina (author)
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy; Centre for Applied Biomedical Research, Alma Mater Studiorum University of Bologna, Via Zamboni, 33, Bologna, 40126 Italy
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- Sanese, Paola (author)
- Medical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis' Research Hospital, 70013 Bari, Italy
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- Forte, Giovanna (author)
- Medical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis' Research Hospital, 70013 Bari, Italy
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- Signorile, Martina Lepore (author)
- Medical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis' Research Hospital, 70013 Bari, Italy
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- Barril, Xavier (author)
- Institut de Biomedicina de la Universitat de Barcelona (IBUB) and Facultat de Farmacia, Universitat de Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain
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- Simone, Cristiano (author)
- Medical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis' Research Hospital, 70013 Bari, Italy; Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, 70124 Bari, Italy
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- Bartolini, Manuela (author)
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
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- Dobritzsch, Doreen, 1972- (author)
- Uppsala universitet,Biokemi
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- Del Rio, Alberto (author)
- Institute for Organic Synthesis and Photoreactivity, National Research Council, Via P. Gobetti 101, 40129 Bologna, Italy; Innovamol Consulting Srl, Via Giardini 470/H, 41124 Modena, Italy
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- Danielson, U. Helena, Professor, 1959- (author)
- Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2021-02-11
- 2021
- English.
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In: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 22:9, s. 1597-1608
- Related links:
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https://chemistry-eu...
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- SMYD3 is a multifunctional epigenetic enzyme with lysine methyl transferase activity and various interaction partners. It is implicated in the pathophysiology of cancers but with an unclear mechanism. To discover tool compounds for clarifying its biochemistry and potential as a therapeutic target, a set of drug-like compounds was screened using a biosensor-based competition assay. Diperodon was identified as an allosteric ligand. The ( R )-and ( S )-enantiomers of the racemic drug were isolated and their affinities determined ( K D > = 42 and 84 ÎŒM). Co-crystallization revealed that both enantiomers bind to a previously unidentified allosteric site in the C-terminal protein binding domain, consistent with its weak inhibitory effect. No competition between diperodon and HSP90 (a known SMYD3 interaction partner) was observed although HSP90-SMYD3 binding was confirmed ( K D = 13 ÎŒM). The allosteric site appears to be druggable and suitable for exploration of non-catalytic SMYD3 functions and therapeutics with new mechanisms of action.
Subject headings
- NATURVETENSKAP -- Biologi -- Biofysik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biophysics (hsv//eng)
Keyword
- SMYD3
- Lysine methyl transferase
- Surface plasmon resonance
- screening
- diperodon
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Talibov, Vladimi ...
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Fabini, Edoardo
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FitzGerald, Edwa ...
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Tedesco, Daniele
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Cederfelt, Danie ...
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Talu, Martin J
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show more...
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Rachman, Moira M
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Mihalic, Filip
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Manoni, Elisabet ...
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Naldi, Marina
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Sanese, Paola
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Forte, Giovanna
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Signorile, Marti ...
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Barril, Xavier
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Simone, Cristian ...
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Bartolini, Manue ...
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Dobritzsch, Dore ...
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Del Rio, Alberto
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Danielson, U. He ...
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biophysics
- Articles in the publication
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ChemBioChem
- By the university
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Uppsala University