2qlq

File:2qlq.jpg

spinqualitylabelsall models 2qlq, resolution 2.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of src kinase with covalent inhibitor XXX

OverviewOverview

Resistance to kinase- targeted cancer drugs has recently been linked to a single point mutation in the ATP binding site of the kinase. In EGFR, the crucial Thr790 gatekeeper residue is mutated to a Met and prevents reversible ATP competitive inhibitors from binding. Irreversible 4-(phenylamino)quinazolines have been shown to overcome this drug resistance and are currently in clinical trials. In order to obtain a detailed structural understanding of how irreversible inhibitors overcome drug resistance, we used Src kinase as a model system for drug resistant EGFR-T790M. We report the first crystal structure of a drug resistant kinase in complex with an irreversible inhibitor. This 4-(phenylamino)quinazoline inhibits wild type and drug resistant EGFR in vitro at low nM concentrations. The co-crystal structure of drug resistant cSrc-T338M kinase domain provides the structural basis of this activity.

About this StructureAbout this Structure

2QLQ is a Single protein structure of sequence from Gallus gallus with as ligand. Active as Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Known structural/functional Sites: , and . Full crystallographic information is available from OCA.

ReferenceReference

Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR., Michalczyk A, Kluter S, Rode HB, Simard JR, Grutter C, Rabiller M, Rauh D, Bioorg Med Chem. 2008 Feb 20;. PMID:18316192

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