2QLQ

Crystal structure of SRC kinase domain with covalent inhibitor RL3

Summary for 2QLQ

• Entry DOI: 10.2210/pdb2qlq/pdb
• Related: 2HWP 2QI8 2QIG 2QQ7
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, (2E)-N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide (3 entities in total)
• Functional Keywords: src kinase domain, drug resistance, irreversible inhibitor, kovalent inhibitor, alternative splicing, atp-binding, lipoprotein, myristate, nucleotide-binding, phosphorylation, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase
• Biological source: Gallus gallus (chicken)
• Cellular location: Cell membrane (By similarity): P00523
• Total number of polymer chains: 2
• Total formula weight: 66764.35

Authors

Michalczyk, A.,Rode, H.B.,Gruetter, C.,Rauh, D. (deposition date: 2007-07-13, release date: 2008-03-11, Last modification date: 2024-11-13)

Primary citation

Michalczyk, A.,Kluter, S.,Rode, H.B.,Simard, J.R.,Grutter, C.,Rabiller, M.,Rauh, D.
Structural insights into how irreversible inhibitors can overcome drug resistance in EGFR.
Bioorg.Med.Chem., 16:3482-3488, 2008

PubMed Abstract: 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.

PubMed: 18316192
DOI: 10.1016/j.bmc.2008.02.053

Experimental method

X-RAY DIFFRACTION (2.33 Å)