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spinqualitylabelsall models 2oiq, resolution 2.07Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of chicken c-Src kinase domain in complex with the cancer drug imatinib.

Overview

The cancer drug imatinib inhibits the tyrosine kinases c-Abl, c-Kit, and, the PDGF receptor. Imatinib is less effective against c-Src, which is, difficult to understand because residues interacting with imatinib in, crystal structures of Abl and c-Kit are conserved in c-Src. The crystal, structure of the c-Src kinase domain in complex with imatinib closely, resembles that of Abl*imatinib and c-Kit*imatinib, and differs, significantly from the inactive "Src/CDK" conformation of the Src family, kinases. Attempts to increase the affinity of c-Src for imatinib by, swapping residues with the corresponding residues in Abl have not been, successful, suggesting that the thermodynamic penalty for adoption of the, imatinib-binding conformation by c-Src is distributed over a broad region, of the structure. Two mutations that are expected to destabilize the, inactive Src/CDK conformation increase drug sensitivity 15-fold, suggesting that the free-energy balance between different inactive states, is a key to imatinib binding.

About this Structure

2OIQ is a Single protein structure of sequence from Gallus gallus with STI and GOL as ligands. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Full crystallographic information is available from OCA.

Reference

c-Src Binds to the Cancer Drug Imatinib with an Inactive Abl/c-Kit Conformation and a Distributed Thermodynamic Penalty., Seeliger MA, Nagar B, Frank F, Cao X, Henderson MN, Kuriyan J, Structure. 2007 Mar;15(3):299-311. PMID:17355866

Page seeded by OCA on Wed Nov 21 13:12:07 2007