4J97

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

4J97 の概要

• エントリーDOI: 10.2210/pdb4j97/pdb
• 関連するPDBエントリー: 2PSQ 2PVF 4J95 4J96 4J98 4J99
• 分子名称: Fibroblast growth factor receptor 2, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: kinase domain fold consisting of n- and c-lobes, receptor tyrosine kinase, atp binding, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: 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
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 150943.21

構造登録者

Chen, H.,Mohammadi, M. (登録日: 2013-02-15, 公開日: 2013-08-07, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.5482 Å)