2itu
From Proteopedia
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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]], [[2itn|2ITN]], [[2ito|2ITO]], [[2itp|2ITP]], [[2itq|2ITQ]], [[2itt|2ITT]], [[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=2itu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2itu OCA], [http://www.ebi.ac.uk/pdbsum/2itu PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2itu 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. | ||
| - | |||
| - | ==Disease== | ||
| - | Known diseases associated with this structure: Adenocarcinoma of lung, response to tyrosine kinase inhibitor in OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=131550 131550]], Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=131550 131550]], Nonsmall cell lung cancer, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=131550 131550]] | ||
==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: STU]] | ||
[[Category: afn941]] | [[Category: afn941]] | ||
[[Category: alternative splicing]] | [[Category: alternative splicing]] | ||
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[[Category: transmembrane]] | [[Category: transmembrane]] | ||
| - | ''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 03:48:31 2008'' |
Revision as of 00:48, 31 March 2008
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| , resolution 2.80Å | |||||||
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| Sites: | |||||||
| Ligands: | |||||||
| Related: | 1DNQ, 1DNR, 1IVO, 1M14, 1M17, 1MOX, 1NQL, 1XKK, 1YY9, 1Z9I, 2ITN, 2ITO, 2ITP, 2ITQ, 2ITT, 2ITV, 2ITW, 2ITX, 2ITY, 2ITZ
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH AFN941
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.
About this Structure
2ITU is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity., Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ, Cancer Cell. 2007 Mar;11(3):217-27. PMID:17349580
Page seeded by OCA on Mon Mar 31 03:48:31 2008
Categories: Homo sapiens | Single protein | Boggon, T J. | Eck, M J. | Greulich, H. | Li, Y. | Meyerson, M. | Woo, S. | Yun, C H. | Afn941 | Alternative splicing | Anti-oncogene | Atp-binding | Cell cycle | Disease mutation | Egfr | Epidermal growth factor | Glycoprotein | L858r | Membrane tyrosine-protein kinase | Nucleotide-binding | Phosphorylation | Polymorphism | Receptor | Staurosporine | Transferase | Transmembrane
