1r0p: Difference between revisions

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[[Image:1r0p.gif|left|200px]]
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[[Image:1r0p.png|left|200px]]


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{{STRUCTURE_1r0p|  PDB=1r0p  |  SCENE=  }}  
{{STRUCTURE_1r0p|  PDB=1r0p  |  SCENE=  }}  


'''Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met in complex with the microbial alkaloid K-252a'''
===Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met in complex with the microbial alkaloid K-252a===




==Overview==
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The protooncogene c-met codes for the hepatocyte growth factor receptor tyrosine kinase. Binding of its ligand, hepatocyte growth factor/scatter factor, stimulates receptor autophosphorylation, which leads to pleiotropic downstream signaling events in epithelial cells, including cell growth, motility, and invasion. These events are mediated by interaction of cytoplasmic effectors, generally through Src homology 2 (SH2) domains, with two phosphotyrosine-containing sequence motifs in the unique C-terminal tail of c-Met (supersite). There is a strong link between aberrant c-Met activity and oncogenesis, which makes this kinase an important cancer drug target. The furanosylated indolocarbazole K-252a belongs to a family of microbial alkaloids that also includes staurosporine. It was recently shown to be a potent inhibitor of c-Met. Here we report the crystal structures of an unphosphorylated c-Met kinase domain harboring a human cancer mutation and its complex with K-252a at 1.8-A resolution. The structure follows the well established architecture of protein kinases. It adopts a unique, inhibitory conformation of the activation loop, a catalytically noncompetent orientation of helix alphaC, and reveals the complete C-terminal docking site. The first SH2-binding motif (1349YVHV) adopts an extended conformation, whereas the second motif (1356YVNV), a binding site for Grb2-SH2, folds as a type II Beta-turn. The intermediate portion of the supersite (1353NATY) assumes a type I Beta-turn conformation as in an Shc-phosphotyrosine binding domain peptide complex. K-252a is bound in the adenosine pocket with an analogous binding mode to those observed in previously reported structures of protein kinases in complex with staurosporine.
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{{ABSTRACT_PUBMED_14559966}}


==Disease==
==Disease==
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[[Category: Shc]]
[[Category: Shc]]
[[Category: Signal transduction]]
[[Category: Signal transduction]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 06:55:57 2008''
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 16:54:51 2008''

Revision as of 13:54, 28 July 2008

File:1r0p.png


Drag the structure with the mouse to rotate
1r0p, resolution 1.80Å (default scene)
Ligands: KSA
Gene: MET (Homo sapiens)
Activity: Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml



Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met in complex with the microbial alkaloid K-252a

Template:ABSTRACT PUBMED 14559966

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

1R0P is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a., Schiering N, Knapp S, Marconi M, Flocco MM, Cui J, Perego R, Rusconi L, Cristiani C, Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12654-9. Epub 2003 Oct 14. PMID:14559966

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