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dc.contributor.authorJones, AM
dc.contributor.authorWestwood, IM
dc.contributor.authorOsborne, JD
dc.contributor.authorMatthews, TP
dc.contributor.authorCheeseman, MD
dc.contributor.authorRowlands, MG
dc.contributor.authorJeganathan, F
dc.contributor.authorBurke, R
dc.contributor.authorLee, D
dc.contributor.authorKadi, N
dc.contributor.authorLiu, M
dc.contributor.authorRichards, M
dc.contributor.authorMcAndrew, C
dc.contributor.authorYahya, N
dc.contributor.authorDobson, SE
dc.contributor.authorJones, K
dc.contributor.authorWorkman, P
dc.contributor.authorCollins, I
dc.contributor.authorvan Montfort, RLM
dc.date.accessioned2016-10-19T16:20:22Z
dc.date.issued2016-10-06
dc.identifier.citationScientific reports, 2016, 6 pp. 34701 - ?
dc.identifier.issn2045-2322
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/177
dc.identifier.eissn2045-2322
dc.identifier.doi10.1038/srep34701
dc.description.abstractThe heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors. Crystal structures of amino-quinazoline ligands bound to the different conformational states of the HSP70 nucleotide binding domain highlighted the challenges of a fragment-based approach when applied to this particular flexible enzyme class with an ATP-binding site that changes shape and size during its catalytic cycle. In these studies we showed that Ser275 is a key residue in the selective binding of ATP. Additionally, the structural data revealed a potential functional role for the ATP ribose moiety in priming the protein for the formation of the ATP-bound pre-hydrolysis complex by influencing the conformation of one of the phosphate binding loops.
dc.formatElectronic
dc.format.extent34701 - ?
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectQuinazolines
dc.subjectProtein Isoforms
dc.subjectLigands
dc.subjectCrystallography, X-Ray
dc.subjectBinding Sites
dc.subjectAmino Acid Sequence
dc.subjectProtein Conformation
dc.subjectProtein Binding
dc.subjectProtein Folding
dc.subjectDrug Design
dc.subjectModels, Molecular
dc.subjectHSP70 Heat-Shock Proteins
dc.titleA fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.
dc.typeJournal Article
dcterms.dateAccepted2016-09-15
rioxxterms.versionofrecord10.1038/srep34701
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-10-06
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfScientific reports
pubs.notesNot known
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/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
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/Hit Discovery & Structural Design
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 2
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design
pubs.publication-statusPublished
pubs.volume6
pubs.embargo.termsNot known
icr.researchteamMedicinal Chemistry 2en_US
icr.researchteamMedicinal Chemistry 3en_US
icr.researchteamHit Discovery & Structural Designen_US
dc.contributor.icrauthorBurke, Rosemaryen
dc.contributor.icrauthorCheeseman, Matthewen
dc.contributor.icrauthorMatthews, Thomasen
dc.contributor.icrauthorVan Montfort, Roberten
dc.contributor.icrauthorWorkman, Paulen
dc.contributor.icrauthorCollins, Ianen
dc.contributor.icrauthorJones, Keithen


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