4CKJ

Crystal structure of RET tyrosine kinase domain bound to adenosine

4CKJ の概要

• エントリーDOI: 10.2210/pdb4ckj/pdb
• 関連するPDBエントリー: 4CKI
• 分子名称: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET, ADENOSINE, FORMIC ACID, ... (4 entities in total)
• 機能のキーワード: 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 : P07949
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36791.86

構造登録者

Plaza-Menacho, I.,Barnouin, K.,Goodman, K.,Martinez-Torres, R.J.,Borg, A.,Murray-Rust, J.,Mouilleron, S.,Knowles, P.,McDonald, N.Q. (登録日: 2014-01-06, 公開日: 2014-03-05, 最終更新日: 2024-11-13)

主引用文献

Plaza-Menacho, I.,Barnouin, K.,Goodman, K.,Martinez-Torres, R.J.,Borg, A.,Murray-Rust, J.,Mouilleron, S.,Knowles, P.,McDonald, N.Q.
Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans.
Mol. Cell, 53:738-751, 2014

PubMed Abstract: To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that late autophosphorylation sites become phosphorylated much earlier than wild-type RET, which is due to a combination of an enhanced enzymatic activity, increased ATP affinity, and surprisingly, by providing a better intermolecular substrate. Structural analysis of oncogenic M918T and wild-type RET kinase domains reveal a cis-inhibitory mechanism involving tethering contacts between the glycine-rich loop, activation loop, and αC-helix. Tether mutations only affected substrate presentation but perturbed the autophosphorylation trajectory similar to oncogenic mutations. This study reveals an unappreciated role for oncogenic RET kinase mutations in promoting intermolecular autophosphorylation by enhancing substrate presentation.

PubMed: 24560924
DOI: 10.1016/j.molcel.2014.01.015

実験手法

X-RAY DIFFRACTION (1.65 Å)