5a46

Publication Abstract from PubMed

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 alphaH helix, towards the outstanding stability of the DFG-out complex with the inhibitor ponatinib. We conclude that the alphaC-beta4 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.

Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase.,Klein T, Vajpai N, Phillips JJ, Davies G, Holdgate GA, Phillips C, Tucker JA, Norman RA, Scott AD, Higazi DR, Lowe D, Thompson GS, Breeze AL Nat Commun. 2015 Jul 23;6:7877. doi: 10.1038/ncomms8877. PMID:26203596^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.