title: Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.
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.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, MA 02115, USA.
authors.forename: Cai-Hong
authors.initials: CH
authors.lastname: Yun
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Li
authors.forename: Michele S
authors.initials: MS
authors.lastname: Woo
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011687:Purines / Q000737:chemistry; D011799:Quinazolines / Q000737:chemistry; D019311:Staurosporine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: C519151:AFN941; D000970:Antineoplastic Agents; D011687:Purines; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors; C489254:AEE 788; D019311:Staurosporine; D000077156:Gefitinib