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Sökning: onr:"swepub:oai:DiVA.org:uu-429944" > Discovery of an all...

Discovery of an allosteric ligand binding site in SMYD3 lysine methyltransferase

Talibov, Vladimir O, 1991- (författare)
Uppsala universitet,Biokemi
Fabini, Edoardo (författare)
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
FitzGerald, Edward (författare)
Uppsala universitet,Biokemi,Beact Therapeut AB, Virdings Alle 2, S-75450 Uppsala, Sweden
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Tedesco, Daniele (författare)
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
Cederfelt, Daniela (författare)
Uppsala universitet,Biokemi
Talu, Martin J (författare)
Uppsala universitet,Biokemi
Rachman, Moira M (författare)
Institut de Biomedicina de la Universitat de Barcelona (IBUB) and Facultat de Farmacia, Universitat de Barcelona, Av. Joan XXIII 27–31, 08028 Barcelona, Spain
Mihalic, Filip (författare)
Uppsala universitet,Biokemi
Manoni, Elisabetta (författare)
Institute for Organic Synthesis and Photoreactivity, National Research Council, Via P. Gobetti 101, 40129 Bologna, Italy
Naldi, Marina (författare)
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
Sanese, Paola (författare)
Medical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis' Research Hospital, 70013 Bari, Italy
Forte, Giovanna (författare)
Medical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis' Research Hospital, 70013 Bari, Italy
Signorile, Martina Lepore (författare)
Medical Genetics, National Institute for Gastroenterology, IRCCS ‘S. de Bellis' Research Hospital, 70013 Bari, Italy
Barril, Xavier (författare)
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
Simone, Cristiano (författare)
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
Bartolini, Manuela (författare)
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy
Dobritzsch, Doreen, 1972- (författare)
Uppsala universitet,Biokemi
Del Rio, Alberto (författare)
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
Danielson, U. Helena, Professor, 1959- (författare)
Uppsala universitet,Biokemi,Science for Life Laboratory, SciLifeLab
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 (creator_code:org_t)
2021-02-11
2021
Engelska.
Ingår i: ChemBioChem. - : Wiley. - 1439-4227 .- 1439-7633. ; 22:9, s. 1597-1608
Relaterad länk:
https://chemistry-eu...
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https://uu.diva-port... (primary) (Raw object)
https://doi.org/10.1...
https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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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.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biofysik (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biophysics (hsv//eng)

Nyckelord

SMYD3
Lysine methyl transferase
Surface plasmon resonance
screening
diperodon

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