1R1W

CRYSTAL STRUCTURE OF THE TYROSINE KINASE DOMAIN OF THE HEPATOCYTE GROWTH FACTOR RECEPTOR C-MET

Summary for 1R1W

• Entry DOI: 10.2210/pdb1r1w/pdb
• Related: 1r0p
• Descriptor: HEPATOCYTE GROWTH FACTOR RECEPTOR (2 entities in total)
• Functional Keywords: receptor tyrosine kinase, signal transduction, grb2, shc, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein. Isoform 3: Secreted: P08581
• Total number of polymer chains: 1
• Total formula weight: 35306.90

Authors

Schiering, N.,Knapp, S.,Marconi, M.,Flocco, M.M.,Cui, J.,Perego, R.,Rusconi, L.,Cristiani, C. (deposition date: 2003-09-25, release date: 2003-10-07, Last modification date: 2023-08-23)

Primary citation

Schiering, N.,Knapp, S.,Marconi, M.,Flocco, M.M.,Cui, J.,Perego, R.,Rusconi, L.,Cristiani, C.
Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-Met and its complex with the microbial alkaloid K-252a
Proc.Natl.Acad.Sci.USA, 100:12654-12659, 2003

PubMed Abstract: 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.

PubMed: 14559966
DOI: 10.1073/pnas.1734128100

Experimental method

X-RAY DIFFRACTION (1.8 Å)