2itp: Difference between revisions
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[[Image:2itp.jpg|left|200px]]<br /><applet load="2itp" size=" | [[Image:2itp.jpg|left|200px]]<br /><applet load="2itp" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="2itp, resolution 2.74Å" /> | caption="2itp, resolution 2.74Å" /> | ||
'''CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN G719S MUTATION IN COMPLEX WITH AEE788'''<br /> | '''CRYSTAL STRUCTURE OF EGFR KINASE DOMAIN G719S MUTATION IN COMPLEX WITH AEE788'''<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== | ||
2ITP 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 AEE as [http://en.wikipedia.org/wiki/ligand ligand]. 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: <scene name='pdbsite=AC1:Aee Binding Site For | 2ITP 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=AEE:'>AEE</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. 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: <scene name='pdbsite=AC1:Aee Binding Site For Residue A 2019'>AC1</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2ITP 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: tyrosine-protein kinase]] | [[Category: tyrosine-protein kinase]] | ||
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