Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70

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Autor(es): dc.contributorThe Institute of Cancer Research-
Autor(es): dc.contributorKeele University-
Autor(es): dc.contributorAlbert Einstein College of Medicine-
Autor(es): dc.contributorUniversity of Birmingham-
Autor(es): dc.contributorUniversidade Estadual Paulista (UNESP)-
Autor(es): dc.creatorO’connor, Suzanne-
Autor(es): dc.creatorLe Bihan, Yann-Vaï-
Autor(es): dc.creatorWestwood, Isaac M.-
Autor(es): dc.creatorLiu, Manjuan-
Autor(es): dc.creatorMak, Oi Wei-
Autor(es): dc.creatorZazeri, Gabriel-
Autor(es): dc.creatorPovinelli, Ana P. R.-
Autor(es): dc.creatorJones, Alan M.-
Autor(es): dc.creatorvan Montfort, Rob-
Autor(es): dc.creatorReynisson, Jóhannes-
Autor(es): dc.creatorCollins, Ian-
Data de aceite: dc.date.accessioned2025-08-21T20:56:24Z-
Data de disponibilização: dc.date.available2025-08-21T20:56:24Z-
Data de envio: dc.date.issued2022-04-29-
Data de envio: dc.date.issued2022-04-29-
Data de envio: dc.date.issued2022-01-31-
Fonte completa do material: dc.identifierhttp://dx.doi.org/10.3390/molecules27030817-
Fonte completa do material: dc.identifierhttp://hdl.handle.net/11449/230279-
Fonte: dc.identifier.urihttp://educapes.capes.gov.br/handle/11449/230279-
Descrição: dc.descriptionHeat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromo-lar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series.-
Descrição: dc.descriptionCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)-
Descrição: dc.descriptionCancer Research UK Cancer Therapeutics Unit The Institute of Cancer Research-
Descrição: dc.descriptionSchool of Pharmacy and Bioengineering Keele University-
Descrição: dc.descriptionDepartment of Biochemistry Albert Einstein College of Medicine-
Descrição: dc.descriptionSchool of Pharmacy Institute of Clinical Sciences College of Medical and Dental Sciences University of Birmingham, Edgbaston-
Descrição: dc.descriptionDepartamento de Física Instituto de Biociências Letras e Ciências Exatas (IBILCE) UNESP, Rua Cristovão Colombo 2265-
Descrição: dc.descriptionDepartamento de Física Instituto de Biociências Letras e Ciências Exatas (IBILCE) UNESP, Rua Cristovão Colombo 2265-
Descrição: dc.descriptionCAPES: 001-
Idioma: dc.languageen-
Relação: dc.relationMolecules-
???dc.source???: dc.sourceScopus-
Palavras-chave: dc.subjectCryptic pocket-
Palavras-chave: dc.subjectFragment screen-
Palavras-chave: dc.subjectHSP70-
Palavras-chave: dc.subjectMolecular dynamics-
Palavras-chave: dc.subjectVirtual screen-
Título: dc.titleDiscovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70-
Tipo de arquivo: dc.typelivro digital-
Aparece nas coleções:Repositório Institucional - Unesp

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