2itq: Difference between revisions
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|SITE= <scene name='pdbsite=AC1:Stu+Binding+Site+For+Residue+A+2019'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Stu+Binding+Site+For+Residue+A+2019'>AC1</scene> | ||
|LIGAND= <scene name='pdbligand=STU:STAUROSPORINE'>STU</scene> | |LIGAND= <scene name='pdbligand=STU:STAUROSPORINE'>STU</scene> | ||
|ACTIVITY= [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span> | ||
|GENE= | |GENE= | ||
|DOMAIN= | |||
|RELATEDENTRY=[[1dnq|1DNQ]], [[1dnr|1DNR]], [[1ivo|1IVO]], [[1m14|1M14]], [[1m17|1M17]], [[1mox|1MOX]], [[1nql|1NQL]], [[1xkk|1XKK]], [[1yy9|1YY9]], [[1z9i|1Z9I]], [[2itn|2ITN]], [[2ito|2ITO]], [[2itp|2ITP]], [[2itt|2ITT]], [[2itu|2ITU]], [[2itv|2ITV]], [[2itw|2ITW]], [[2itx|2ITX]], [[2ity|2ITY]], [[2itz|2ITZ]] | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2itq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2itq OCA], [http://www.ebi.ac.uk/pdbsum/2itq PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2itq 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: afn941]] | [[Category: afn941]] | ||
[[Category: alternative splicing]] | [[Category: alternative splicing]] | ||
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[[Category: tyrosine-protein kinase]] | [[Category: tyrosine-protein kinase]] | ||
''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 03:48:30 2008'' | ||