2X2K

Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor

2X2K の概要

• エントリーDOI: 10.2210/pdb2x2k/pdb
• 関連するPDBエントリー: 2IVS 2IVT 2IVU 2IVV 2X2L 2X2M
• 分子名称: PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET, FORMIC ACID, (3Z)-5-amino-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one, ... (4 entities in total)
• 機能のキーワード: tyrosine kinase, hirschsprung disease, tyrosine-protein kinase, proto-oncogene, phosphoprotein, transferase, phosphotransferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 36179.59

構造登録者

Knowles, P.P.,Murray-Rust, J.,Kjaer, S.,McDonald, N.Q. (登録日: 2010-01-13, 公開日: 2010-02-09, 最終更新日: 2024-11-13)

主引用文献

Mologni, L.,Rostagno, R.,Brussolo, S.,Knowles, P.P.,Kjaer, S.,Murray-Rust, J.,Rosso, E.,Zambon, A.,Scapozza, L.,McDonald, N.Q.,Lucchini, V.,Gambacorti-Passerini, C.
Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
Bioorg. Med. Chem., 18:1482-1496, 2010

PubMed Abstract: The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers.

PubMed: 20117004
DOI: 10.1016/j.bmc.2010.01.011

実験手法

X-RAY DIFFRACTION (2.6 Å)