2rfn: Difference between revisions

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[[Image:2rfn.jpg|left|200px]]
[[Image:2rfn.jpg|left|200px]]


{{Structure
<!--
|PDB= 2rfn |SIZE=350|CAPTION= <scene name='initialview01'>2rfn</scene>, resolution 2.50&Aring;
The line below this paragraph, containing "STRUCTURE_2rfn", creates the "Structure Box" on the page.
|SITE=
You may change the PDB parameter (which sets the PDB file loaded into the applet)  
|LIGAND= <scene name='pdbligand=AM7:2-BENZYL-5-(3-FLUORO-4-{[6-METHOXY-7-(3-MORPHOLIN-4-YLPROPOXY)QUINOLIN-4-YL]OXY}PHENYL)-3-METHYLPYRIMIDIN-4(3H)-ONE'>AM7</scene>
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
|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>
or leave the SCENE parameter empty for the default display.
|GENE= MET ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
-->
|DOMAIN=
{{STRUCTURE_2rfn| PDB=2rfn  | SCENE= }}  
|RELATEDENTRY=[[2rfs|2RFS]]
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2rfn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rfn OCA], [http://www.ebi.ac.uk/pdbsum/2rfn PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2rfn RCSB]</span>
}}


'''x-ray structure of c-Met with inhibitor.'''
'''x-ray structure of c-Met with inhibitor.'''


==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==
==Disease==
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==About this Structure==
==About this Structure==
2RFN 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=2RFN OCA].  
2RFN 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=2RFN 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:[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.]]
[[Category: atp-binding]]
[[Category: Atp-binding]]
[[Category: c-met hgf receptor tyrosine kinse kinase domain]]
[[Category: C-met hgf receptor tyrosine kinse kinase domain]]
[[Category: glycoprotein]]
[[Category: Glycoprotein]]
[[Category: membrane]]
[[Category: Membrane]]
[[Category: nucleotide-binding]]
[[Category: Nucleotide-binding]]
[[Category: phosphorylation]]
[[Category: Phosphorylation]]
[[Category: proto-oncogene]]
[[Category: Proto-oncogene]]
[[Category: transferase]]
[[Category: Transferase]]
[[Category: transmembrane]]
[[Category: Transmembrane]]
[[Category: tyrosine-protein kinase]]
[[Category: Tyrosine-protein kinase]]
 
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:00:01 2008''
Retrieved from "https://proteopedia.org/2rfn"