5A4C

FGFR1 ligand complex

Summary for 5A4C

• Entry DOI: 10.2210/pdb5a4c/pdb
• Related: 5A46
• Descriptor: FIBROBLAST GROWTH FACTOR RECEPTOR 1 (FMS-RELATED TYROSINE KINASE 2, PFEIFFER SYNDROME), ISOFORM CRA_B, SULFATE ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: transferase, kinase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P11362
• Total number of polymer chains: 2
• Total formula weight: 72174.65

Authors

Klein, T.,Vajpai, N.,Phillips, J.J.,Davies, G.,Holdgate, G.A.,Phillips, C.,Tucker, J.A.,Norman, R.A.,Scott, A.S.,Higazi, D.R.,Lowe, D.,Thompson, G.S.,Breeze, A.L. (deposition date: 2015-06-05, release date: 2015-08-05, Last modification date: 2024-05-08)

Primary citation

Klein, T.,Vajpai, N.,Phillips, J.J.,Davies, G.,Holdgate, G.A.,Phillips, C.,Tucker, J.A.,Norman, R.A.,Scott, A.D.,Higazi, D.R.,Lowe, D.,Thompson, G.S.,Breeze, A.L.
Structural and Dynamic Insights Into the Energetics of Activation Loop Rearrangement in Fgfr1 Kinase.
Nat.Commun., 6:7877-, 2015

PubMed 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.

PubMed: 26203596
DOI: 10.1038/NCOMMS8877

Experimental method

X-RAY DIFFRACTION (2.09 Å)