2v7a

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spinqualitylabelsall models 2v7a, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURE OF THE T315I ABL MUTANT IN COMPLEX WITH THE INHIBITOR PHA-739358

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Mutations in the kinase domain of Bcr-Abl are the most common cause of, resistance to therapy with imatinib in patients with chronic myelogenous, leukemia (CML). Second-generation Bcr-Abl inhibitors are able to overcome, most imatinib-resistant mutants, with the exception of the frequent T315I, substitution, which is emerging as a major cause of resistance to these, drugs in CML patients. Structural studies could be used to support the, drug design process for the development of inhibitors able to target the, T315I substitution, but until now no crystal structure of the T315I Abl, mutant has been solved. We show here the first crystal structure of the, kinase domain of Abl T315I in complex with PHA-739358, an Aurora kinase, inhibitor currently in clinical development for solid and hematologic, malignancies. This compound inhibits in vitro the kinase activity of, wild-type Abl and of several mutants, including T315I. The cocrystal, structure of T315I Abl kinase domain provides the structural basis for, this activity: the inhibitor associates with an active conformation of the, kinase domain in the ATP-binding pocket and lacks the steric hindrance, imposed by the substitution of threonine by isoleucine. [Cancer Res, 2007;67(17):7987-90].

Disease

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

About this Structure

2V7A is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Crystal Structure of the T315I Abl Mutant in Complex with the Aurora Kinases Inhibitor PHA-739358., Modugno M, Casale E, Soncini C, Rosettani P, Colombo R, Lupi R, Rusconi L, Fancelli D, Carpinelli P, Cameron AD, Isacchi A, Moll J, Cancer Res. 2007 Sep 1;67(17):7987-90. PMID:17804707

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