1m52

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spinqualitylabelsall models 1m52, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of the c-Abl Kinase domain in complex with PD173955

Overview

The inadvertent fusion of the bcr gene with the abl gene results in a, constitutively active tyrosine kinase (Bcr-Abl) that transforms cells and, causes chronic myelogenous leukemia. Small molecule inhibitors of Bcr-Abl, that bind to the kinase domain can be used to treat chronic myelogenous, leukemia. We report crystal structures of the kinase domain of Abl in, complex with two such inhibitors, imatinib (also known as STI-571 and, Gleevec) and PD173955 (Parke-Davis). Both compounds bind to the canonical, ATP-binding site of the kinase domain, but they do so in different ways., As shown previously in a crystal structure of Abl bound to a smaller, variant of STI-571, STI-571 captures a specific inactive conformation of, the activation loop of Abl in which the loop mimics bound peptide, substrate. In contrast, PD173955 binds to a conformation of Abl in which, the activation loop resembles that of an active kinase. The structure, suggests that PD173955 would be insensitive to whether the conformation of, the activation loop corresponds to active kinases or to that seen in the, STI-571 complex. In vitro kinase assays confirm that this is the case and, indicate that PD173955 is at least 10-fold more inhibitory than STI-571., The structures suggest that PD173955 achieves its greater potency over, STI-571 by being able to target multiple forms of Abl (active or, inactive), whereas STI-571 requires a specific inactive conformation of, Abl.

About this Structure

1M52 is a Single protein structure of sequence from Mus musculus with MES and P17 as ligands. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.

Reference

Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571)., Nagar B, Bornmann WG, Pellicena P, Schindler T, Veach DR, Miller WT, Clarkson B, Kuriyan J, Cancer Res. 2002 Aug 1;62(15):4236-43. PMID:12154025

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