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

التفاصيل البيبلوغرافية
العنوان: Discovery and Characterization of a Cryptic Secondary Binding Site in the Molecular Chaperone HSP70.
المؤلفون: O'Connor S; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK., Le Bihan YV; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK., Westwood IM; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK., Liu M; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK., Mak OW; School of Pharmacy and Bioengineering, Keele University, Keele ST5 5BG, UK.; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Zazeri G; School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.; Departamento de Física, Instituto de Biociências, Letras e Ciências Exatas (IBILCE), UNESP, Rua Cristovão Colombo 2265, São José do Rio Preto 15054-000, Brazil., Povinelli APR; School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.; Departamento de Física, Instituto de Biociências, Letras e Ciências Exatas (IBILCE), UNESP, Rua Cristovão Colombo 2265, São José do Rio Preto 15054-000, Brazil., Jones AM; School of Pharmacy, Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., van Montfort R; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK., Reynisson J; School of Pharmacy and Bioengineering, Keele University, Keele ST5 5BG, UK., Collins I; Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
المصدر: Molecules (Basel, Switzerland) [Molecules] 2022 Jan 26; Vol. 27 (3). Date of Electronic Publication: 2022 Jan 26.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Basel, Switzerland : MDPI, c1995-
مواضيع طبية MeSH: HSP70 Heat-Shock Proteins/*antagonists & inhibitors , HSP70 Heat-Shock Proteins/*metabolism , Small Molecule Libraries/*chemistry , Small Molecule Libraries/*pharmacology, Adenosine Triphosphate/metabolism ; Binding Sites/drug effects ; Drug Discovery ; HSP70 Heat-Shock Proteins/chemistry ; Humans ; Ligands ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Protein Domains/drug effects
مستخلص: Heat 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 micromolar 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.
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معلومات مُعتمدة: 22897 United Kingdom CRUK_ Cancer Research UK; C309/A11566 United Kingdom CRUK_ Cancer Research UK
فهرسة مساهمة: Keywords: HSP70; cryptic pocket; fragment screen; molecular dynamics; virtual screen
المشرفين على المادة: 0 (HSP70 Heat-Shock Proteins)
0 (Ligands)
0 (Small Molecule Libraries)
8L70Q75FXE (Adenosine Triphosphate)
تواريخ الأحداث: Date Created: 20220215 Date Completed: 20220223 Latest Revision: 20240210
رمز التحديث: 20240210
مُعرف محوري في PubMed: PMC8839746
DOI: 10.3390/molecules27030817
PMID: 35164081
قاعدة البيانات: MEDLINE
الوصف
تدمد:1420-3049
DOI:10.3390/molecules27030817