dc.contributor.author | Darby, JF | |
dc.contributor.author | Vidler, LR | |
dc.contributor.author | Simpson, PJ | |
dc.contributor.author | Al-Lazikani, B | |
dc.contributor.author | Matthews, SJ | |
dc.contributor.author | Sharp, SY | |
dc.contributor.author | Pearl, LH | |
dc.contributor.author | Hoelder, S | |
dc.contributor.author | Workman, P | |
dc.date.accessioned | 2020-10-07T11:49:32Z | |
dc.date.issued | 2020-09-29 | |
dc.identifier.citation | Scientific reports, 2020, 10 (1), pp. 16000 - ? | |
dc.identifier.issn | 2045-2322 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4129 | |
dc.identifier.eissn | 2045-2322 | |
dc.identifier.doi | 10.1038/s41598-020-71969-w | |
dc.description.abstract | Heat shock protein 90 (Hsp90) is a molecular chaperone that plays an important role in tumour biology by promoting the stabilisation and activity of oncogenic 'client' proteins. Inhibition of Hsp90 by small-molecule drugs, acting via its ATP hydrolysis site, has shown promise as a molecularly targeted cancer therapy. Owing to the importance of Hop and other tetratricopeptide repeat (TPR)-containing cochaperones in regulating Hsp90 activity, the Hsp90-TPR domain interface is an alternative site for inhibitors, which could result in effects distinct from ATP site binders. The TPR binding site of Hsp90 cochaperones includes a shallow, positively charged groove that poses a significant challenge for druggability. Herein, we report the apo, solution-state structure of Hop TPR2A which enables this target for NMR-based screening approaches. We have designed prototype TPR ligands that mimic key native 'carboxylate clamp' interactions between Hsp90 and its TPR cochaperones and show that they block binding between Hop TPR2A and the Hsp90 C-terminal MEEVD peptide. We confirm direct TPR-binding of these ligands by mapping 1H-15N HSQC chemical shift perturbations to our new NMR structure. Our work provides a novel structure, a thorough assessment of druggability and robust screening approaches that may offer a potential route, albeit difficult, to address the chemically challenging nature of the Hop TPR2A target, with relevance to other TPR domain interactors. | |
dc.format | Electronic | |
dc.format.extent | 16000 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Heat-Shock Proteins | |
dc.subject | Ligands | |
dc.subject | Nuclear Magnetic Resonance, Biomolecular | |
dc.subject | Catalytic Domain | |
dc.subject | Protein Conformation | |
dc.subject | Protein Binding | |
dc.subject | Models, Molecular | |
dc.subject | Computer Simulation | |
dc.subject | Small Molecule Libraries | |
dc.subject | Protein Domains | |
dc.title | Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-08-24 | |
rioxxterms.versionofrecord | 10.1038/s41598-020-71969-w | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-09-29 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Scientific reports | |
pubs.issue | 1 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Computational Biology and Chemogenomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4 (including Analytical Chemistry) | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Computational Biology and Chemogenomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4 (including Analytical Chemistry) | |
pubs.publication-status | Published | |
pubs.volume | 10 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Computational Biology and Chemogenomics | |
icr.researchteam | Medicinal Chemistry 4 (including Analytical Chemistry) | |
dc.contributor.icrauthor | Al-Lazikani, Bissan | |
dc.contributor.icrauthor | Pearl, Laurence | |
dc.contributor.icrauthor | Hoelder, Swen | |
dc.contributor.icrauthor | Workman, Paul | |