2itz: Difference between revisions
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[[Image:2itz.jpg|left|200px]]<br /><applet load="2itz" size=" | [[Image:2itz.jpg|left|200px]]<br /><applet load="2itz" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2itz, resolution 2.80Å" /> | caption="2itz, resolution 2.80Å" /> | ||
'''CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH IRESSA'''<br /> | '''CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH IRESSA'''<br /> | ||
==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. | |||
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2ITZ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CL and IRE as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Site | 2ITZ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=CL:'>CL</scene> and <scene name='pdbligand=IRE:'>IRE</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Sites: <scene name='pdbsite=AC1:Cl Binding Site For Residue A 2020'>AC1</scene> and <scene name='pdbsite=AC2:Ire Binding Site For Residue A 2021'>AC2</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ITZ 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17349580 17349580] | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Receptor protein-tyrosine kinase]] | [[Category: Receptor protein-tyrosine kinase]] | ||
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[[Category: zd1839]] | [[Category: zd1839]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Jan 31 10:57:04 2008'' | ||
Revision as of 11:57, 31 January 2008
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CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN L858R MUTATION IN COMPLEX WITH IRESSA
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Adenocarcinoma of lung, response to tyrosine kinase inhibitor in OMIM:[131550], Nonsmall cell lung cancer, response to tyrosine kinase inhibitor in OMIM:[131550], Nonsmall cell lung cancer, susceptibility to OMIM:[131550]
About this StructureAbout this Structure
2ITZ is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Receptor protein-tyrosine kinase, with EC number 2.7.10.1 Known structural/functional Sites: and . Full crystallographic information is available from OCA.
ReferenceReference
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 Thu Jan 31 10:57:04 2008
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- Homo sapiens
- Receptor protein-tyrosine kinase
- Single protein
- Boggon, T.J.
- Eck, M.J.
- Greulich, H.
- Li, Y.
- Meyerson, M.
- Woo, S.
- Yun, C.H.
- CL
- IRE
- Alternative splicing
- Anti-oncogene
- Atp-binding
- Cell cycle
- Disease mutation
- Egfr
- Epidermal growth factor
- Gefitinib
- Glycoprotein
- Iressa
- L858r
- Membrane
- Nucleotide-binding
- Phosphorylation
- Polymorphism
- Receptor
- Transferase
- Transmembrane
- Tyrosine-protein kinase
- Zd1839