2QQ7
Crystal structure of drug resistant SRC kinase domain with irreversible inhibitor
Summary for 2QQ7
Entry DOI | 10.2210/pdb2qq7/pdb |
Related | 2HWP 2QI8 2QIG 2QLQ |
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, 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 | 66398.22 |
Authors | Michalczyk, A.,Rode, H.B.,Gruetter, C.,Rauh, D. (deposition date: 2007-07-26, release date: 2008-03-11, Last modification date: 2024-10-16) |
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 Cited by 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: 18316192DOI: 10.1016/j.bmc.2008.02.053 PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.38 Å) |
Structure validation
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