Structure-based design of a covalent Inhibitor of the SET domain-containing protein 8 (SETD8) lysine methyltransferase

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Autor(es): dc.contributorDepartment of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Estados Unidos-
Autor(es): dc.contributorStructural Genomics Consortium, Universidade de Toronto, Toronto, Ontário M5G 1L7, Canadá-
Autor(es): dc.contributorMolecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, Estados Unidos-
Autor(es): dc.contributorDepartment of Pharmacology and Toxicology, University of Toronto, Toronto, Ontário M5S 1A8, Canadá-
Autor(es): dc.creatorButler, Kyle V.-
Autor(es): dc.creatorAnqi Ma-
Autor(es): dc.creatorWenyu Yu-
Autor(es): dc.creatorFengling Li-
Autor(es): dc.creatorTempel, Wolfram-
Autor(es): dc.creatorBabault, Nicolas-
Autor(es): dc.creatorPittella-Silva, Fabio-
Autor(es): dc.creatorShao, Jason-
Autor(es): dc.creatorJunyi Wang-
Autor(es): dc.creatorMinkui Luo-
Autor(es): dc.creatorVedadi, Masoud-
Autor(es): dc.creatorBrown, Peter J.-
Autor(es): dc.creatorArrowsmith, Cheryl H.-
Autor(es): dc.creatorJian Jin-
Data de aceite: dc.date.accessioned2024-07-22T12:26:13Z-
Data de disponibilização: dc.date.available2024-07-22T12:26:13Z-
Data de envio: dc.date.issued2022-10-04-
Data de envio: dc.date.issued2022-10-04-
Data de envio: dc.date.issued2016-
Fonte completa do material: dc.identifierhttps://repositorio.unb.br/handle/10482/44981-
Fonte completa do material: dc.identifierhttps://doi.org/10.1021/acs.jmedchem.6b01244-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/capes/803624-
Descrição: dc.descriptionSelective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC50 value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases. We also solved the crystal structure of the covalent inhibitor in complex with SETD8. This work provides atomic-level perspective on the inhibition of SETD8 by small molecules and will help identify high-quality chemical probes of SETD8.-
Publicador: dc.publisherAmerican Chemical Society-
Relação: dc.relationhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.6b01244#-
Direitos: dc.rightsAcesso Restrito-
Palavras-chave: dc.subjectAdutos-
Palavras-chave: dc.subjectEstrutura cristalina-
Palavras-chave: dc.subjectInibidores-
Palavras-chave: dc.subjectMonômeros-
Palavras-chave: dc.subjectPeptídeos-
Palavras-chave: dc.subjectProteínas-
Título: dc.titleStructure-based design of a covalent Inhibitor of the SET domain-containing protein 8 (SETD8) lysine methyltransferase-
Aparece nas coleções:Repositório Institucional – UNB

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