Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Export

@article{citeulike:1284089, abstract = {Mutations in the EGFR kinase are a cause of non-small-cell lung cancer. To understand their mechanism of activation and effects on drug binding, we studied the kinetics of the L858R and G719S mutants and determined their crystal structures with inhibitors including gefitinib, AEE788, and a staurosporine. We find that the mutations activate the kinase by disrupting autoinhibitory interactions, and that they accelerate catalysis as much as 50-fold in vitro. Structures of inhibitors in complex with both wild-type and mutant kinases reveal similar binding modes for gefitinib and AEE788, but a marked rotation of the staurosporine in the G719S mutant. Strikingly, direct binding measurements show that gefitinib binds 20-fold more tightly to the L858R mutant than to the wild-type enzyme.}, address = {Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, MA 02115, USA.}, author = {Yun, C. H. and Boggon, T. J. and Li, Y. and Woo, M. S. and Greulich, H. and Meyerson, M. and Eck, M. J.}, citeulike-article-id = {1284089}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.ccr.2006.12.017}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/17349580}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=17349580}, doi = {10.1016/j.ccr.2006.12.017}, issn = {1535-6108}, journal = {Cancer Cell}, keywords = {40061085, analisis, armaduras, cables, estructural, estructuras, estructure, marcos, puentes, vias, vigas}, month = {March}, number = {3}, pages = {217--227}, posted-at = {2007-05-11 21:39:24}, priority = {1}, title = {Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.}, url = {http://dx.doi.org/10.1016/j.ccr.2006.12.017}, volume = {11}, year = {2007} }

TY - JOUR ID - citeulike:1284089 L3 - citeulike-article-id:1284089 N2 - Mutations in the EGFR kinase are a cause of non-small-cell lung cancer. To understand their mechanism of activation and effects on drug binding, we studied the kinetics of the L858R and G719S mutants and determined their crystal structures with inhibitors including gefitinib, AEE788, and a staurosporine. We find that the mutations activate the kinase by disrupting autoinhibitory interactions, and that they accelerate catalysis as much as 50-fold in vitro. Structures of inhibitors in complex with both wild-type and mutant kinases reveal similar binding modes for gefitinib and AEE788, but a marked rotation of the staurosporine in the G719S mutant. Strikingly, direct binding measurements show that gefitinib binds 20-fold more tightly to the L858R mutant than to the wild-type enzyme. IS - 3 JF - Cancer Cell SN - 1535-6108 AD - Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, MA 02115, USA. EP - 227 TI - Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. VL - 11 SP - 217 KW - 40061085 KW - analisis KW - armaduras KW - cables KW - estructural KW - estructuras KW - estructure KW - marcos KW - puentes KW - vias KW - vigas AU - Yun, CH AU - Boggon, TJ AU - Li, Y AU - Woo, MS AU - Greulich, H AU - Meyerson, M AU - Eck, MJ PY - 2007/03// UR - http://dx.doi.org/10.1016/j.ccr.2006.12.017 ER -