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PDBsum entry 5a4c
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PDB id:
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Transferase
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Title:
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Fgfr1 ligand complex
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Structure:
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Fibroblast growth factor receptor 1 (fms-related tyrosine kinase 2, pfeiffer syndrome), isoform cra_b. Chain: a, b. Fragment: residues 461-765. Synonym: fgfr1. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.09Å
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R-factor:
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0.197
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R-free:
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0.235
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Authors:
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T.Klein,N.Vajpai,J.J.Phillips,G.Davies,G.A.Holdgate,C.Phillips, J.A.Tucker,R.A.Norman,A.S.Scott,D.R.Higazi,D.Lowe,G.S.Thompson, A.L.Breeze
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Key ref:
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T.Klein
et al.
(2015).
Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase.
Nat Commun,
6,
7877.
PubMed id:
DOI:
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Date:
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05-Jun-15
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Release date:
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05-Aug-15
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PROCHECK
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Headers
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References
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P11362
(FGFR1_HUMAN) -
Fibroblast growth factor receptor 1 from Homo sapiens
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Seq:
Struc:
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822 a.a.
294 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.2.7.10.1
- receptor protein-tyrosine kinase.
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Reaction:
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L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
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L-tyrosyl-[protein]
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+
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ATP
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=
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O-phospho-L-tyrosyl-[protein]
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Nat Commun
6:7877
(2015)
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PubMed id:
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Structural and dynamic insights into the energetics of activation loop rearrangement in FGFR1 kinase.
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T.Klein,
N.Vajpai,
J.J.Phillips,
G.Davies,
G.A.Holdgate,
C.Phillips,
J.A.Tucker,
R.A.Norman,
A.D.Scott,
D.R.Higazi,
D.Lowe,
G.S.Thompson,
A.L.Breeze.
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ABSTRACT
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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.
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