2g15: Difference between revisions

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-[[Image:2g15.gif|left|200px]]
- {{Structure
+==Structural Characterization of autoinhibited c-Met kinase==
-|PDB= 2g15 |SIZE=350|CAPTION= <scene name='initialview01'>2g15</scene>, resolution 2.15&Aring;
+<StructureSection load='2g15' size='340' side='right'caption='[[2g15]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
-|SITE=
+== Structural highlights ==
-|LIGAND=
+<table><tr><td colspan='2'>[[2g15]] 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=2G15 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2G15 FirstGlance]. <br>
-|ACTIVITY=
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15&#8491;</td></tr>
-|GENE=
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2g15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g15 OCA], [https://pdbe.org/2g15 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2g15 RCSB], [https://www.ebi.ac.uk/pdbsum/2g15 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2g15 ProSAT]</span></td></tr>
-|DOMAIN=
+</table>
-|RELATEDENTRY=
+== Disease ==
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2g15 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2g15 OCA], [http://www.ebi.ac.uk/pdbsum/2g15 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2g15 RCSB]</span>
+[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/g1/2g15_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=2g15 ConSurf].
+<div style="clear:both"></div>
-'''Structural Characterization of autoinhibited c-Met kinase'''
+==See Also==
+*[[Hepatocyte growth factor receptor 3D structures|Hepatocyte growth factor receptor 3D structures]]
+== References ==
-==Overview==
+<references/>
-Protein kinases are a large family of cell signaling mediators undergoing intensive research to identify inhibitors or modulators useful for medicine. As one strategy, small-molecule compounds that bind the active site with high affinity can be used to inhibit the enzyme activity. X-ray crystallography is a powerful method to reveal the structures of the kinase active sites, and thus aid in the design of high-affinity, selective inhibitors. However, a limitation still exists in the ability to produce purified kinases in amounts sufficient for crystallography. Furthermore, kinases exist in different conformation states as part of their normal regulation, and the ability to prepare crystals of kinases in these various states also remains a limitation. In this study, the c-Abl, c-Src, and c-Met kinases are produced in high yields in Escherichia coli by using a bicistronic vector encoding the PTP1B tyrosine phosphatase. A 100-fold lower dose of the inhibitor, Imatinib, was observed to inhibit the unphosphorylated form of c-Abl kinase prepared by using this vector, compared to the phosphorylated form produced without PTP1B, consistent with the known selectivity of this inhibitor for the unactivated conformation of the enzyme. Unphosphorylated c-Met kinase produced with this vector was used to obtain the crystal structure, at 2.15-A resolution, of the autoinhibited form of the kinase domain, revealing an intricate network of interactions involving c-Met residues documented previously to cause dysregulation when mutated in several cancers.
+__TOC__
+</StructureSection>
-==About this Structure==
-G15 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=2G15 OCA].
-==Reference==
-Structural characterization of autoinhibited c-Met kinase produced by coexpression in bacteria with phosphatase., Wang W, Marimuthu A, Tsai J, Kumar A, Krupka HI, Zhang C, Powell B, Suzuki Y, Nguyen H, Tabrizizad M, Luu C, West BL, Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3563-8. Epub 2006 Feb 28. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16537444 16537444]
 [[Category: Homo sapiens]]
-[[Category: Single protein]]
+[[Category: Large Structures]]
-[[Category: Krupka, H I.]]
+[[Category: Krupka HI]]
-[[Category: Kumar, A.]]
+[[Category: Kumar A]]
-[[Category: Luu, C.]]
+[[Category: Luu C]]
-[[Category: Marimuthu, A.]]
+[[Category: Marimuthu A]]
-[[Category: Nguyen, H.]]
+[[Category: Nguyen H]]
-[[Category: Powell, B.]]
+[[Category: Powell B]]
-[[Category: Suzuki, Y.]]
+[[Category: Suzuki Y]]
-[[Category: Tabrizizad, M.]]
+[[Category: Tabrizizad M]]
-[[Category: Tsai, J.]]
+[[Category: Tsai J]]
-[[Category: Wang, W.]]
+[[Category: Wang W]]
-[[Category: West, B L.]]
+[[Category: West BL]]
-[[Category: Zhang, C.]]
+[[Category: Zhang C]]
-[[Category: kinase domain]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:10:27 2008''