dc.contributor.author | Klein, T | |
dc.contributor.author | Vajpai, N | |
dc.contributor.author | Phillips, JJ | |
dc.contributor.author | Davies, G | |
dc.contributor.author | Holdgate, GA | |
dc.contributor.author | Phillips, C | |
dc.contributor.author | Tucker, JA | |
dc.contributor.author | Norman, RA | |
dc.contributor.author | Scott, AD | |
dc.contributor.author | Higazi, DR | |
dc.contributor.author | Lowe, D | |
dc.contributor.author | Thompson, GS | |
dc.contributor.author | Breeze, AL | |
dc.date.accessioned | 2018-10-25T14:19:58Z | |
dc.date.issued | 2015-07-23 | |
dc.description.abstract | Protein 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. | en_GB |
dc.description.sponsorship | This 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. | en_GB |
dc.identifier.citation | Vol. 6, article 7877 | en_GB |
dc.identifier.doi | 10.1038/ncomms8877 | |
dc.identifier.uri | http://hdl.handle.net/10871/34465 | |
dc.language.iso | en | en_GB |
dc.publisher | Springer Nature | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/26203596 | en_GB |
dc.rights | © 2018 The Author(s). Open access. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ | en_GB |
dc.subject | Escherichia coli | en_GB |
dc.subject | Humans | en_GB |
dc.subject | Imidazoles | en_GB |
dc.subject | Kinetics | en_GB |
dc.subject | Magnetic Resonance Spectroscopy | en_GB |
dc.subject | Mass Spectrometry | en_GB |
dc.subject | Molecular Structure | en_GB |
dc.subject | Pyridazines | en_GB |
dc.subject | Receptor, Fibroblast Growth Factor, Type 1 | en_GB |
dc.title | Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-10-25T14:19:58Z | |
exeter.place-of-publication | England | en_GB |
dc.description | This is the final version. Available on open access from Springer Nature via the DOI in this record | en_GB |
dc.identifier.journal | Nature Communications | en_GB |