4J97

Crystal Structure of FGF Receptor 2 (FGFR2) Kinase Domain Harboring the Pathogenic Gain-of-Function K659E Mutation Identified in Endometrial Cancer.

Summary for 4J97

• Entry DOI: 10.2210/pdb4j97/pdb
• Related: 2PSQ 2PVF 4J95 4J96 4J98 4J99
• Descriptor: Fibroblast growth factor receptor 2, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, SULFATE ION, ... (4 entities in total)
• Functional Keywords: kinase domain fold consisting of n- and c-lobes, receptor tyrosine kinase, atp binding, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 3: Cell membrane; Single-pass type I membrane protein. Isoform 14: Secreted. Isoform 19: Secreted: P21802
• Total number of polymer chains: 4
• Total formula weight: 150943.21

Authors

Chen, H.,Mohammadi, M. (deposition date: 2013-02-15, release date: 2013-08-07, Last modification date: 2023-09-20)

Primary citation

Chen, H.,Huang, Z.,Dutta, K.,Blais, S.,Neubert, T.A.,Li, X.,Cowburn, D.,Traaseth, N.J.,Mohammadi, M.
Cracking the Molecular Origin of Intrinsic Tyrosine Kinase Activity through Analysis of Pathogenic Gain-of-Function Mutations.
Cell Rep, 4:376-384, 2013

PubMed Abstract: The basal (ligand-independent) kinase activity of receptor tyrosine kinases (RTKs) promotes trans-phosphorylation on activation loop tyrosines upon ligand-induced receptor dimerization, thus upregulating intrinsic kinase activity and triggering intracellular signaling. To understand the molecular determinants of intrinsic kinase activity, we used X-ray crystallography and NMR spectroscopy to analyze pathogenic FGF receptor mutants with gradations in gain-of-function activity. These structural analyses revealed a "two-state" dynamic equilibrium model whereby the kinase toggles between an "inhibited," structurally rigid ground state and a more dynamic and heterogeneous active state. The pathogenic mutations have different abilities to shift this equilibrium toward the active state. The increase in the fractional population of FGF receptors in the active state correlates with the degree of gain-of-function activity and clinical severity. Our data demonstrate that the fractional population of RTKs in the active state determines intrinsic kinase activity and underscore how a slight increase in the active population of kinases can have grave consequences for human health.

PubMed: 23871672
DOI: 10.1016/j.celrep.2013.06.025

Experimental method

X-RAY DIFFRACTION (2.5482 Å)