2hiw

From Proteopedia

Revision as of 20:26, 12 November 2007

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

Overview

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.

Disease

Known diseases associated with this structure: Leukemia, Philadelphia chromosome-positive, resistant to imatinib OMIM:[189980]

About this Structure

2HIW is a Single protein structure of sequence from Homo sapiens with 7MP as ligand. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Full crystallographic information is available from OCA.

Reference

A general strategy for creating "inactive-conformation" abl inhibitors., Okram B, Nagle A, Adrian FJ, Lee C, Ren P, Wang X, Sim T, Xie Y, Wang X, Xia G, Spraggon G, Warmuth M, Liu Y, Gray NS, Chem Biol. 2006 Jul;13(7):779-86. PMID:16873026

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