6PNX

Crystal Structure of an Asymmetric Dimer of FGF Receptor 3 Kinases Trapped in A-loop Tyrosine Transphosphorylation Reaction

6PNX の概要

• エントリーDOI: 10.2210/pdb6pnx/pdb
• 分子名称: Fibroblast growth factor receptor 3, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: tyrosine kinase, transphosphorylation, asymmetric dimer, 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: 74290.25

構造登録者

Mohammadi, M. (登録日: 2019-07-03, 公開日: 2020-01-22, 最終更新日: 2023-10-11)

主引用文献

Chen, L.,Marsiglia, W.M.,Chen, H.,Katigbak, J.,Erdjument-Bromage, H.,Kemble, D.J.,Fu, L.,Ma, J.,Sun, G.,Zhang, Y.,Liang, G.,Neubert, T.A.,Li, X.,Traaseth, N.J.,Mohammadi, M.
Molecular basis for receptor tyrosine kinase A-loop tyrosine transphosphorylation.
Nat.Chem.Biol., 16:267-277, 2020

PubMed Abstract: A long-standing mystery shrouds the mechanism by which catalytically repressed receptor tyrosine kinase domains accomplish transphosphorylation of activation loop (A-loop) tyrosines. Here we show that this reaction proceeds via an asymmetric complex that is thermodynamically disadvantaged because of an electrostatic repulsion between enzyme and substrate kinases. Under physiological conditions, the energetic gain resulting from ligand-induced dimerization of extracellular domains overcomes this opposing clash, stabilizing the A-loop-transphosphorylating dimer. A unique pathogenic fibroblast growth factor receptor gain-of-function mutation promotes formation of the complex responsible for phosphorylation of A-loop tyrosines by eliminating this repulsive force. We show that asymmetric complex formation induces a more phosphorylatable A-loop conformation in the substrate kinase, which in turn promotes the active state of the enzyme kinase. This explains how quantitative differences in the stability of ligand-induced extracellular dimerization promotes formation of the intracellular A-loop-transphosphorylating asymmetric complex to varying extents, thereby modulating intracellular kinase activity and signaling intensity.

PubMed: 31959966
DOI: 10.1038/s41589-019-0455-7

実験手法

X-RAY DIFFRACTION (2.199 Å)