2j6m: Difference between revisions
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|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY=[[1dnq|1DNQ]], [[1dnr|1DNR]], [[1ivo|1IVO]], [[1m14|1M14]], [[1m17|1M17]], [[1mox|1MOX]], [[1nql|1NQL]], [[1xkk|1XKK]], [[1yy9|1YY9]], [[1z9i|1Z9I]], [[2gs2|2GS2]], [[2gs7|2GS7]], [[2itn|2ITN]], [[2ito|2ITO]], [[2itp|2ITP]], [[2itq|2ITQ]], [[2itt|2ITT]], [[2itu|2ITU]], [[2itv|2ITV]], [[2itw|2ITW]], [[2itx|2ITX]], [[2ity|2ITY]], [[2itz|2ITZ]], [[2j5e|2J5E]], [[2j5f|2J5F]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2j6m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2j6m OCA], [http://www.ebi.ac.uk/pdbsum/2j6m PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2j6m RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
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. | 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. | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Woo, S.]] | [[Category: Woo, S.]] | ||
[[Category: Yun, C H.]] | [[Category: Yun, C H.]] | ||
[[Category: aee788]] | [[Category: aee788]] | ||
[[Category: alternative splicing]] | [[Category: alternative splicing]] | ||
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[[Category: wild-type]] | [[Category: wild-type]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:53:51 2008'' | ||