2rfs

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[[Image:2rfs.jpg|left|200px]]
[[Image:2rfs.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2rfs |SIZE=350|CAPTION= <scene name='initialview01'>2rfs</scene>, resolution 2.20&Aring;
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The line below this paragraph, containing "STRUCTURE_2rfs", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=AM8:N-(3-CHLOROPHENYL)-N-METHYL-2-OXO-3-[(3,4,5-TRIMETHYL-1H-PYRROL-2-YL)METHYL]-2H-INDOLE-5-SULFONAMIDE'>AM8</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|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>
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or leave the SCENE parameter empty for the default display.
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|GENE= MET ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
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-->
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|DOMAIN=
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{{STRUCTURE_2rfs| PDB=2rfs | SCENE= }}
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|RELATEDENTRY=[[2rfn|2RFN]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2rfs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rfs OCA], [http://www.ebi.ac.uk/pdbsum/2rfs PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2rfs RCSB]</span>
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}}
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'''X-ray structure of SU11274 bound to c-Met'''
'''X-ray structure of SU11274 bound to c-Met'''
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==Overview==
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c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.
==Disease==
==Disease==
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==About this Structure==
==About this Structure==
2RFS is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RFS OCA].
2RFS is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RFS OCA].
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==Reference==
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c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations., Bellon SF, Kaplan-Lefko P, Yang Y, Zhang Y, Moriguchi J, Rex K, Johnson CW, Rose PE, Long AM, O'Connor AB, Gu Y, Coxon A, Kim TS, Tasker A, Burgess TL, Dussault I, J Biol Chem. 2008 Feb 1;283(5):2675-83. Epub 2007 Nov 30. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18055465 18055465]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Receptor protein-tyrosine kinase]]
[[Category: Receptor protein-tyrosine kinase]]
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[[Category: Yang, Y.]]
[[Category: Yang, Y.]]
[[Category: Zhang, Y.]]
[[Category: Zhang, Y.]]
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[[Category: atp-binding]]
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[[Category: Atp-binding]]
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[[Category: c-met]]
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[[Category: C-met]]
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[[Category: glycoprotein]]
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[[Category: Glycoprotein]]
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[[Category: membrane]]
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[[Category: Membrane]]
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[[Category: nucleotide-binding]]
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[[Category: Nucleotide-binding]]
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[[Category: phosphorylation]]
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[[Category: Phosphorylation]]
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[[Category: proto-oncogene]]
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[[Category: Proto-oncogene]]
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[[Category: receptor tyrosine kinase]]
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[[Category: Receptor tyrosine kinase]]
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[[Category: su11274]]
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[[Category: Su11274]]
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[[Category: transferase]]
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[[Category: Transferase]]
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[[Category: transmembrane]]
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[[Category: Transmembrane]]
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[[Category: tyrosine-protein kinase]]
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[[Category: Tyrosine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr 16 23:08:16 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:00:05 2008''
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Revision as of 20:08, 16 April 2008

Image:2rfs.jpg

Template:STRUCTURE 2rfs

X-ray structure of SU11274 bound to c-Met


Contents

Overview

c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.

Disease

Known disease associated with this structure: Hepatocellular carcinoma, childhood type OMIM:[164860], Renal cell carcinoma, papillary, familial and sporadic OMIM:[164860], Autism, suseptibility to, 9 OMIM:[164860]

About this Structure

2RFS is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations., Bellon SF, Kaplan-Lefko P, Yang Y, Zhang Y, Moriguchi J, Rex K, Johnson CW, Rose PE, Long AM, O'Connor AB, Gu Y, Coxon A, Kim TS, Tasker A, Burgess TL, Dussault I, J Biol Chem. 2008 Feb 1;283(5):2675-83. Epub 2007 Nov 30. PMID:18055465 Page seeded by OCA on Wed Apr 16 23:08:16 2008

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