2HIW

Crystal Structure of Inactive Conformation Abl Kinase Catalytic Domain Complexed with Type II Inhibitor

2HIW の概要

• エントリーDOI: 10.2210/pdb2hiw/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase ABL1, 7-AMINO-1-METHYL-3-(2-METHYL-5-{[3-(TRIFLUOROMETHYL)BENZOYL]AMINO}PHENYL)-2-OXO-2,3-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1-IUM (3 entities in total)
• 機能のキーワード: kinase domain, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton. Isoform IB: Nucleus membrane; Lipid-anchor: P00519
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67278.69

構造登録者

Lee, C. (登録日: 2006-06-29, 公開日: 2006-08-22, 最終更新日: 2023-08-30)

主引用文献

Okram, B.,Nagle, A.,Adrian, F.J.,Lee, C.,Ren, P.,Wang, X.,Sim, T.,Xie, Y.,Wang, X.,Xia, G.,Spraggon, G.,Warmuth, M.,Liu, Y.,Gray, N.S.
A general strategy for creating
Chem.Biol., 13:779-786, 2006

PubMed Abstract: Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups: those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocket made accessible by a conformational rearrangement of the activation loop (type II). To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational "hybrid-design" approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl.

PubMed: 16873026
DOI: 10.1016/j.chembiol.2006.05.015

実験手法

X-RAY DIFFRACTION (2.2 Å)