5IUI

Crystal Structure of Anaplastic Lyphoma Kinase (ALK) in complex with 4

5IUI の概要

• エントリーDOI: 10.2210/pdb5iui/pdb
• 関連するPDBエントリー: 5IUG 5IUH
• 分子名称: ALK tyrosine kinase receptor, N-[3-(4-amino-3-methylphenyl)-1H-pyrazol-5-yl]-4-[(4-methylpiperazin-1-yl)methyl]benzamide (3 entities in total)
• 機能のキーワード: catalytic domain, transferase
• 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: 37237.71

構造登録者

Tu, C.H.,Wu, S.Y. (登録日: 2016-03-18, 公開日: 2016-05-18, 最終更新日: 2024-03-20)

主引用文献

Tu, C.H.,Lin, W.H.,Peng, Y.H.,Hsu, T.,Wu, J.S.,Chang, C.Y.,Lu, C.T.,Lyu, P.C.,Shih, C.,Jiaang, W.T.,Wu, S.Y.
Pyrazolylamine Derivatives Reveal the Conformational Switching between Type I and Type II Binding Modes of Anaplastic Lymphoma Kinase (ALK).
J.Med.Chem., 59:3906-3919, 2016

PubMed Abstract: Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, αC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure-activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes.

PubMed: 27031565
DOI: 10.1021/acs.jmedchem.6b00106

実験手法

X-RAY DIFFRACTION (1.88 Å)