View source for 5eyd


==Crystal structure of c-Met in complex with AMG 337==
<StructureSection load='5eyd' size='340' side='right'caption='[[5eyd]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5eyd]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5EYD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EYD FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.85&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5T1:6-[(1~{R})-1-[8-FLUORANYL-6-(1-METHYLPYRAZOL-4-YL)-[1,2,4]TRIAZOLO[4,3-A]PYRIDIN-3-YL]ETHYL]-3-(2-METHOXYETHOXY)-1,6-NAPHTHYRIDIN-5-ONE'>5T1</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5eyd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eyd OCA], [https://pdbe.org/5eyd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eyd RCSB], [https://www.ebi.ac.uk/pdbsum/5eyd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eyd ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/MET_HUMAN 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:[https://omim.org/entry/114550 114550].<ref>PMID:9927037</ref>   Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:[https://omim.org/entry/605074 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.<ref>PMID:9140397</ref> <ref>PMID:9563489</ref> <ref>PMID:10433944</ref> <ref>PMID:10417759</ref> <ref>PMID:10327054</ref>   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.<ref>PMID:20949619</ref> 
== Function ==
[https://www.uniprot.org/uniprot/MET_HUMAN 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.<ref>PMID:1846706</ref> <ref>PMID:8182137</ref> <ref>PMID:15314156</ref>   Acts as a receptor for Listeria internalin inlB, mediating entry of the pathogen into cells.<ref>PMID:1846706</ref> <ref>PMID:8182137</ref> <ref>PMID:15314156</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of compound 23 (AMG 337), which demonstrates nanomolar inhibition of MET kinase activity, desirable preclinical pharmacokinetics, significant inhibition of MET phosphorylation in mice, and robust tumor growth inhibition in a MET-dependent mouse efficacy model.

Discovery of (R)-6-(1-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-y l)ethyl)-3-(2-methoxyethoxy)-1,6-naphthyridin-5(6H)-one (AMG 337), a Potent and Selective Inhibitor of MET with High Unbound Target Coverage and Robust In Vivo Antitumor Activity.,Boezio AA, Copeland KW, Rex K, K Albrecht B, Bauer D, Bellon SF, Boezio C, Broome MA, Choquette D, Coxon A, Dussault I, Hirai S, Lewis R, Lin MJ, Lohman J, Liu J, Peterson EA, Potashman M, Shimanovich R, Teffera Y, Whittington DA, Vaida KR, Harmange JC J Med Chem. 2016 Feb 11. PMID:26812066<ref>PMID:26812066</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5eyd" style="background-color:#fffaf0;"></div>

==See Also==
*[[Hepatocyte growth factor receptor 3D structures|Hepatocyte growth factor receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Long AM]]
[[Category: Whittington DA]]