5UI0

Crystal Structure of the Tyrosine Kinase Domain of FGF Receptor 2 harboring an E565A/K659M Double Gain-of-Function Mutation

5UI0 の概要

• エントリーDOI: 10.2210/pdb5ui0/pdb
• 関連するPDBエントリー: 5UGL 5UGX 5UHN
• 分子名称: Fibroblast growth factor receptor 2, CITRATE ANION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: tyrosine kinase domain, gain-of-function mutation, atp analog cell surface receptor, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75088.59

構造登録者

Mohammadi, M.,Chen, H. (登録日: 2017-01-12, 公開日: 2017-02-22, 最終更新日: 2023-10-04)

主引用文献

Chen, H.,Marsiglia, W.M.,Cho, M.K.,Huang, Z.,Deng, J.,Blais, S.P.,Gai, W.,Bhattacharya, S.,Neubert, T.A.,Traaseth, N.J.,Mohammadi, M.
Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases.
Elife, 6:-, 2017

PubMed Abstract: Receptor tyrosine kinase (RTK) signaling is tightly regulated by protein allostery within the intracellular tyrosine kinase domains. Yet the molecular determinants of allosteric connectivity in tyrosine kinase domain are incompletely understood. By means of structural (X-ray and NMR) and functional characterization of pathogenic gain-of-function mutations affecting the FGF receptor (FGFR) tyrosine kinase domain, we elucidated a long-distance allosteric network composed of four interconnected sites termed the 'molecular brake', 'DFG latch', 'A-loop plug', and 'αC tether'. The first three sites repress the kinase from adopting an active conformation, whereas the αC tether promotes the active conformation. The skewed design of this four-site allosteric network imposes tight autoinhibition and accounts for the incomplete mimicry of the activated conformation by pathogenic mutations targeting a single site. Based on the structural similarity shared among RTKs, we propose that this allosteric model for FGFR kinases is applicable to other RTKs.

PubMed: 28166054
DOI: 10.7554/eLife.21137

実験手法

X-RAY DIFFRACTION (2.05 Å)