3l8v
From Proteopedia
Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor C-MET in complex with a biarylamine based inhibitor
Structural highlights
Disease[MET_HUMAN] Note=Activation of MET after rearrangement with the TPR gene produces an oncogenic protein. Note=Defects in MET may be associated with gastric cancer. Defects in MET are a cause of hepatocellular carcinoma (HCC) [MIM:114550].[1] Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:605074]. It is a subtype of renal cell carcinoma tending to show a tubulo-papillary architecture formed by numerous, irregular, finger-like projections of connective tissue. Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into common renal cell carcinoma (clear cell, non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma.[2] [3] [4] [5] [6] Note=A common allele in the promoter region of the MET shows genetic association with susceptibility to autism in some families. Functional assays indicate a decrease in MET promoter activity and altered binding of specific transcription factor complexes. Note=MET activating mutations may be involved in the development of a highly malignant, metastatic syndrome known as cancer of unknown primary origin (CUP) or primary occult malignancy. Systemic neoplastic spread is generally a late event in cancer progression. However, in some instances, distant dissemination arises at a very early stage, so that metastases reach clinical relevance before primary lesions. Sometimes, the primary lesions cannot be identified in spite of the progresses in the diagnosis of malignancies.[7] Function[MET_HUMAN] Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to hepatocyte growth factor/HGF ligand. Regulates many physiological processes including proliferation, scattering, morphogenesis and survival. Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1, SRC, GRB2, STAT3 or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. The RAS-ERK activation is associated with the morphogenetic effects while PI3K/AKT coordinates prosurvival effects. During embryonic development, MET signaling plays a role in gastrulation, development and migration of muscles and neuronal precursors, angiogenesis and kidney formation. In adults, participates in wound healing as well as organ regeneration and tissue remodeling. Promotes also differentiation and proliferation of hematopoietic cells.[8] [9] [10] Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells.[11] [12] [13] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBiarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model. Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors.,Williams DK, Chen XT, Tarby C, Kaltenbach R, Cai ZW, Tokarski JS, An Y, Sack JS, Wautlet B, Gullo-Brown J, Henley BJ, Jeyaseelan R, Kellar K, Manne V, Trainor GL, Lombardo LJ, Fargnoli J, Borzilleri RM Bioorg Med Chem Lett. 2010 May 1;20(9):2998-3002. Epub 2010 Jan 20. PMID:20382527[14] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Receptor protein-tyrosine kinase | Sack, J | Alternative splicing | Atp-binding | Chromosomal rearrangement | Disease mutation | Glycoprotein | Grb2 | Kinase | Membrane | Nucleotide-binding | Phosphoprotein | Polymorphism | Proto-oncogene | Receptor | Receptor tyrosine kinase | Shc | Signal transduction | Transferase | Transmembrane | Tyrosine-protein kinase
