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dc.contributor.authorKlein, Tobiasen
dc.contributor.authorVajpai, Navratnaen
dc.contributor.authorPhillips, Jonathanen
dc.contributor.authorDavies, Garethen
dc.contributor.authorHoldgate, Geoffrey Aen
dc.contributor.authorPhillips, Chrisen
dc.contributor.authorTucker, Julie Aen
dc.contributor.authorNorman, Richard Aen
dc.contributor.authorScott, Andrew Den
dc.contributor.authorHigazi, Daniel Ren
dc.contributor.authorLowe, Daviden
dc.contributor.authorThompson, Gary Sen
dc.contributor.authorBreeze, Alexander Len
dc.date.accessioned2015-09-03T11:05:43Z
dc.date.available2015-09-03T11:05:43Z
dc.date.issued2015-07-23en
dc.identifier.citationNature Communications 2015, 6, 7877. doi:10.1038/ncomms8877en
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/250463
dc.description.abstractProtein tyrosine kinases differ widely in their propensity to undergo rearrangements of the N-terminal Asp–Phe–Gly (DFG) motif of the activation loop, with some, including FGFR1 kinase, appearing refractory to this so-called ‘DFG flip’. Recent inhibitor-bound structures have unexpectedly revealed FGFR1 for the first time in a ‘DFG-out’ state. Here we use conformationally selective inhibitors as chemical probes for interrogation of the structural and dynamic features that appear to govern the DFG flip in FGFR1. Our detailed structural and biophysical insights identify contributions from altered dynamics in distal elements, including the αH helix, towards the outstanding stability of the DFG-out complex with the inhibitor ponatinib. We conclude that the αC-β4 loop and ‘molecular brake’ regions together impose a high energy barrier for this conformational rearrangement, and that this may have significance for maintaining autoinhibition in the non-phosphorylated basal state of FGFR1.
dc.description.sponsorshipThis work was funded as part of the AstraZeneca Internal Postdoctoral program. All authors with the exception of G.S.T. are employees (and stockholders) of AstraZeneca UK Ltd or MedImmune LLC, or were at the time that this study was conducted.
dc.languageEnglishen
dc.language.isoenen
dc.publisherNPG
dc.rightsAttribution 2.0 UK: England & Wales*
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/uk/*
dc.titleStructural and dynamic insights into the free energy barrier for activation loop rearrangement in FGFR1 tyrosine kinaseen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ncomms8877en
prism.number7877en
prism.publicationDate2015en
prism.publicationNameNature Communicationsen
prism.volume6en
dcterms.dateAccepted2015-06-22en
rioxxterms.versionofrecord10.1038/ncomms8877en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-07-23en
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Reviewen
rioxxterms.freetoread.startdate2015-09-03


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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales