2QI8

Crystal structure of drug resistant SRC kinase domain

Summary for 2QI8

• Entry DOI: 10.2210/pdb2qi8/pdb
• Descriptor: Proto-oncogene tyrosine-protein kinase Src, GLYCEROL (3 entities in total)
• Functional Keywords: src kinase domain; drug resistance, signaling protein, transferase
• Biological source: Gallus gallus (chicken)
• Cellular location: Cell membrane (By similarity): P00523
• Total number of polymer chains: 2
• Total formula weight: 65637.70

Authors

Michalczyk, A.,Rode, H.B.,Gruetter, C.,Rauh, D. (deposition date: 2007-07-03, release date: 2008-03-18, Last modification date: 2024-02-21)

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 (2.32 Å)