Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity.
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.
Yun
Cai-Hong
CH
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, MA 02115, USA.
Boggon
Titus J
TJ
Li
Yiqun
Y
Woo
Michele S
MS
Greulich
Heidi
H
Meyerson
Matthew
M
Eck
Michael J
MJ
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
C519151:AFN941; D000970:Antineoplastic Agents; D011687:Purines; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors; C489254:AEE 788; D019311:Staurosporine; D000077156:Gefitinib