3c1x: Difference between revisions

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-[[Image:3c1x.jpg|left|200px]]
-<!--
+==Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-MET in complex with a Pyrrolotriazine based inhibitor==
-The line below this paragraph, containing "STRUCTURE_3c1x", creates the "Structure Box" on the page.
+<StructureSection load='3c1x' size='340' side='right'caption='[[3c1x]], [[Resolution|resolution]] 2.17&Aring;' scene=''>
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
+== Structural highlights ==
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
+<table><tr><td colspan='2'>[[3c1x]] 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=3C1X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3C1X FirstGlance]. <br>
-or leave the SCENE parameter empty for the default display.
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.17&#8491;</td></tr>
--->
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CKK:N-{[4-({5-[(4-AMINOPIPERIDIN-1-YL)METHYL]PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL}OXY)-3-FLUOROPHENYL]CARBAMOYL}-2-(4-FLUOROPHENYL)ACETAMIDE'>CKK</scene></td></tr>
-{{STRUCTURE_3c1x|  PDB=3c1x  |  SCENE=  }}
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3c1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3c1x OCA], [https://pdbe.org/3c1x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3c1x RCSB], [https://www.ebi.ac.uk/pdbsum/3c1x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3c1x 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>
+== Evolutionary Conservation ==
+[[Image:Consurf_key_small.gif|200px|right]]
+Check<jmol>
+  <jmolCheckbox>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c1/3c1x_consurf.spt"</scriptWhenChecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <text>to colour the structure by Evolutionary Conservation</text>
+  </jmolCheckbox>
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3c1x ConSurf].
+<div style="clear:both"></div>
-'''Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-MET in complex with a Pyrrolotriazine based inhibitor'''
+==See Also==
+*[[Hepatocyte growth factor receptor 3D structures|Hepatocyte growth factor receptor 3D structures]]
+== References ==
-==Overview==
+<references/>
-An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
+__TOC__
+</StructureSection>
-==Disease==
-Known disease associated with this structure: Hepatocellular carcinoma, childhood type OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164860 164860]], Renal cell carcinoma, papillary, familial and sporadic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164860 164860]], Autism, suseptibility to, 9 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164860 164860]]
-==About this Structure==
-C1X 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=3C1X OCA].
-==Reference==
-Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase., Schroeder GM, Chen XT, Williams DK, Nirschl DS, Cai ZW, Wei D, Tokarski JS, An Y, Sack J, Chen Z, Huynh T, Vaccaro W, Poss M, Wautlet B, Gullo-Brown J, Kellar K, Manne V, Hunt JT, Wong TW, Lombardo LJ, Fargnoli J, Borzilleri RM, Bioorg Med Chem Lett. 2008 Mar 15;18(6):1945-51. Epub 2008 Feb 7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18289854 18289854]
 [[Category: Homo sapiens]]
-[[Category: Receptor protein-tyrosine kinase]]
+[[Category: Large Structures]]
-[[Category: Single protein]]
+[[Category: Sack J]]
-[[Category: Sack, J.]]
-[[Category: Atp-binding]]
-[[Category: Glycoprotein]]
-[[Category: Grb2]]
-[[Category: Membrane]]
-[[Category: Nucleotide-binding]]
-[[Category: Phosphoprotein]]
-[[Category: Proto-oncogene]]
-[[Category: Receptor tyrosine kinase]]
-[[Category: Shc]]
-[[Category: Signal transduction]]
-[[Category: Transferase]]
-[[Category: Transmembrane]]
-[[Category: Tyrosine-protein kinase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 21:17:44 2008''