Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase

Tobias Klein, Navratna Vajpai, Jonathan J. Phillips, Gareth Davies, Geoffrey A. Holdgate, Chris Phillips, Julie A. Tucker, Richard A. Norman, Andrew D. Scott, Daniel R. Higazi, David Lowe, Gary S. Thompson and Alexander L. Breeze ()
Additional contact information
Tobias Klein: Discovery Sciences, AstraZeneca R&D
Navratna Vajpai: Discovery Sciences, AstraZeneca R&D
Jonathan J. Phillips: MedImmune
Gareth Davies: Discovery Sciences, AstraZeneca R&D
Geoffrey A. Holdgate: Discovery Sciences, AstraZeneca R&D
Chris Phillips: Discovery Sciences, AstraZeneca R&D
Julie A. Tucker: Discovery Sciences, AstraZeneca R&D
Richard A. Norman: Discovery Sciences, AstraZeneca R&D
Andrew D. Scott: Discovery Sciences, AstraZeneca R&D
Daniel R. Higazi: MedImmune
David Lowe: MedImmune
Gary S. Thompson: Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds
Alexander L. Breeze: Discovery Sciences, AstraZeneca R&D

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8877

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