3zbx - Revision history

OCA at 10:58, 20 December 2023

OCA — Wed, 20 Dec 2023 10:58:29 GMT

←Older revision		Revision as of 10:58, 20 December 2023
Line 3:		Line 3:
	<StructureSection load='3zbx' size='340' side='right'caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='3zbx' size='340' side='right'caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3zbx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZBX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZBX FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3zbx]] 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=3ZBX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZBX FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=6XE:6~~-[[~~6-(4-FLUOROPHENYL)-[1,2,4~~]~~TRIAZOLO[4,3-B~~]~~[1,~~2~~,4]TRIAZIN-3-YL]METHYL]QUINOLINE'>6XE</scene>~~</td></tr>	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.2Å</td></tr>
-	<tr id='~~activity~~'><td class="sblockLbl"><b>~~Activity~~:</b></td><td class="sblockDat"><~~span class~~='~~plainlinks'>[https~~:~~//en.wikipedia.org/wiki/Receptor_protein~~-~~tyrosine_kinase Receptor protein~~-~~tyrosine kinase]~~, ~~with EC number~~ [~~https://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=2.7.10.~~1 2~~.7.10.1~~] </~~span~~></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6XE:6-[[6-(4-FLUOROPHENYL)-[1,2,4]TRIAZOLO[4,3-B][1,2,4]TRIAZIN-3-YL]METHYL]QUINOLINE'>6XE</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=3zbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zbx OCA], [https://pdbe.org/3zbx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zbx RCSB], [https://www.ebi.ac.uk/pdbsum/3zbx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zbx ProSAT]</span></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=3zbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zbx OCA], [https://pdbe.org/3zbx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zbx RCSB], [https://www.ebi.ac.uk/pdbsum/3zbx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zbx ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== 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>	+	[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 ==		== 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>	+	[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 28:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: McTigue M]]
-	[[Category: McTigue, M]]	+	[[Category: Ryan K]]
-	[[Category: Ryan, K]]	+	[[Category: Wickersham J]]
-	[[Category: Wickersham, J]]	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 05:41, 10 August 2022

OCA — Wed, 10 Aug 2022 05:41:18 GMT

←Older revision		Revision as of 05:41, 10 August 2022
Line 3:		Line 3:
	<StructureSection load='3zbx' size='340' side='right'caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='3zbx' size='340' side='right'caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3zbx]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZBX OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3ZBX FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3zbx]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZBX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZBX FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6XE:6-[[6-(4-FLUOROPHENYL)-[1,2,4]TRIAZOLO[4,3-B][1,2,4]TRIAZIN-3-YL]METHYL]QUINOLINE'>6XE</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6XE:6-[[6-(4-FLUOROPHENYL)-[1,2,4]TRIAZOLO[4,3-B][1,2,4]TRIAZIN-3-YL]METHYL]QUINOLINE'>6XE</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [~~http~~://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3zbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zbx OCA], [~~http~~://pdbe.org/3zbx PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3zbx RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3zbx PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3zbx ProSAT]</span></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=3zbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zbx OCA], [https://pdbe.org/3zbx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zbx RCSB], [https://www.ebi.ac.uk/pdbsum/3zbx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zbx ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
-	[[~~http~~://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:[~~http~~://omim.org/entry/114550 114550]].<ref>PMID:9927037</ref> Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:[~~http~~://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>	+	[[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 ==		== Function ==
-	[[~~http~~://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>	+	[[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 23:

	==See Also==		==See Also==
-	*[[Hepatocyte growth factor receptor\|Hepatocyte growth factor receptor]]	+	*[[Hepatocyte growth factor receptor 3D structures\|Hepatocyte growth factor receptor 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:30, 10 May 2019

OCA — Fri, 10 May 2019 12:30:09 GMT

←Older revision		Revision as of 12:30, 10 May 2019
Line 1:		Line 1:

	==X-ray Structure of c-Met kinase in complex with inhibitor 6-((6-(4- fluorophenyl)-(1,2,4)triazolo(4,3-b)(1,2,4)triazin-3-yl)methyl) quinoline.==		==X-ray Structure of c-Met kinase in complex with inhibitor 6-((6-(4- fluorophenyl)-(1,2,4)triazolo(4,3-b)(1,2,4)triazin-3-yl)methyl) quinoline.==
-	<StructureSection load='3zbx' size='340' side='right' caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>	+	<StructureSection load='3zbx' size='340' side='right'caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3zbx]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZBX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZBX FirstGlance]. <br>		<table><tr><td colspan='2'>[[3zbx]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZBX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZBX FirstGlance]. <br>
Line 29:		Line 29:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: McTigue, M]]		[[Category: McTigue, M]]

OCA at 10:11, 4 August 2016

OCA — Thu, 04 Aug 2016 10:11:59 GMT

←Older revision		Revision as of 10:11, 4 August 2016
Line 1:		Line 1:
		+
	==X-ray Structure of c-Met kinase in complex with inhibitor 6-((6-(4- fluorophenyl)-(1,2,4)triazolo(4,3-b)(1,2,4)triazin-3-yl)methyl) quinoline.==		==X-ray Structure of c-Met kinase in complex with inhibitor 6-((6-(4- fluorophenyl)-(1,2,4)triazolo(4,3-b)(1,2,4)triazin-3-yl)methyl) quinoline.==
	<StructureSection load='3zbx' size='340' side='right' caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='3zbx' size='340' side='right' caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6XE:6-[[6-(4-FLUOROPHENYL)-[1,2,4]TRIAZOLO[4,3-B][1,2,4]TRIAZIN-3-YL]METHYL]QUINOLINE'>6XE</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6XE:6-[[6-(4-FLUOROPHENYL)-[1,2,4]TRIAZOLO[4,3-B][1,2,4]TRIAZIN-3-YL]METHYL]QUINOLINE'>6XE</scene></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3zbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zbx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zbx RCSB], [http://www.ebi.ac.uk/pdbsum/3zbx PDBsum]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3zbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zbx OCA], [http://pdbe.org/3zbx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3zbx RCSB], [http://www.ebi.ac.uk/pdbsum/3zbx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3zbx ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
Line 19:		Line 20:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 3zbx" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 16:55, 21 December 2014

OCA — Sun, 21 Dec 2014 16:55:04 GMT

←Older revision		Revision as of 16:55, 21 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_3zbx\| PDB=3zbx \| SCENE= }}~~	+	==X-ray Structure of c-Met kinase in complex with inhibitor 6-((6-(4- fluorophenyl)-(1,2,4)triazolo(4,3-b)(1,2,4)triazin-3-yl)methyl) quinoline.==
-	===X-ray Structure of c-Met kinase in complex with inhibitor 6-((6-(4- fluorophenyl)-(1,2,4)triazolo(4,3-b)(1,2,4)triazin-3-yl)methyl) quinoline.===	+	<StructureSection load='3zbx' size='340' side='right' caption='[[3zbx]], [[Resolution\|resolution]] 2.20Å' scene=''>
-	~~{{ABSTRACT_PUBMED_23944843}}~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[3zbx]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZBX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZBX FirstGlance]. <br>
-	==Disease==	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6XE:6-[[6-(4-FLUOROPHENYL)-[1,2,4]TRIAZOLO[4,3-B][1,2,4]TRIAZIN-3-YL]METHYL]QUINOLINE'>6XE</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3zbx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zbx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zbx RCSB], [http://www.ebi.ac.uk/pdbsum/3zbx PDBsum]</span></td></tr>
		+	</table>
		+	== Disease ==
	[[http://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:[http://omim.org/entry/114550 114550]].<ref>PMID:9927037</ref> Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:[http://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>		[[http://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:[http://omim.org/entry/114550 114550]].<ref>PMID:9927037</ref> Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:[http://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 ==
		+	[[http://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 ==
		+	The hepatocyte growth factor (HGF)/c-Met signaling axis is deregulated in many cancers and plays important roles in tumor invasive growth and metastasis. An exclusively selective c-Met inhibitor (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl )quinoline (8) was discovered from a highly selective high-throughput screening hit via structure-based drug design and medicinal chemistry lead optimization. Compound 8 had many attractive properties meriting preclinical evaluation. Broad off-target screens identified 8 as a pan-phosphodiesterase (PDE) family inhibitor, which was implicated in a sustained increase in heart rate, increased cardiac output, and decreased contractility indices, as well as myocardial degeneration in in vivo safety evaluations in rats. Compound 8 was terminated as a preclinical candidate because of a narrow therapeutic window in cardio-related safety. The learning from multiparameter lead optimization and strategies to avoid the toxicity attrition at the late stage of drug discovery are discussed.

-	~~==Function==~~	+	Lessons from (S)-6-(1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethyl )quinoline (PF-04254644), an inhibitor of receptor tyrosine kinase c-Met with high protein kinase selectivity but broad phosphodiesterase family inhibition leading to myocardial degeneration in rats.,Cui JJ, Shen H, Tran-Dube M, Nambu M, McTigue M, Grodsky N, Ryan K, Yamazaki S, Aguirre S, Parker M, Li Q, Zou H, Christensen J J Med Chem. 2013 Sep 12;56(17):6651-65. doi: 10.1021/jm400926x. Epub 2013 Aug 29. PMID:23944843<ref>PMID:23944843</ref>
-	[[~~http://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>	+

-	~~==About this Structure==~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[3zbx]] is~~ a ~~1 chain structure~~. ~~Full crystallographic information is available from [http://oca~~.~~weizmann~~.~~ac.il~~/~~oca-bin/ocashort?id=3ZBX OCA].~~	+	</div>

-	==~~Reference~~==	+	==See Also==
-	~~<ref group~~=~~"xtra">PMID:023944843</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	*[[Hepatocyte growth factor receptor\|Hepatocyte growth factor receptor]]
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: McTigue, M.]]	+	[[Category: McTigue, M]]
-	[[Category: Ryan, K.]]	+	[[Category: Ryan, K]]
-	[[Category: Wickersham, J.]]	+	[[Category: Wickersham, J]]
	[[Category: Inhibitor]]		[[Category: Inhibitor]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 10:25, 27 November 2013

OCA — Wed, 27 Nov 2013 10:25:06 GMT

←Older revision		Revision as of 10:25, 27 November 2013
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	{{STRUCTURE_3zbx\| PDB=3zbx \| SCENE= }}
		+	===X-ray Structure of c-Met kinase in complex with inhibitor 6-((6-(4- fluorophenyl)-(1,2,4)triazolo(4,3-b)(1,2,4)triazin-3-yl)methyl) quinoline.===
		+	{{ABSTRACT_PUBMED_23944843}}

-	~~The~~ entry ~~3zbx~~ is ~~ON HOLD~~ ~~until Paper Publication~~	+	==Disease==
		+	[[http://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:[http://omim.org/entry/114550 114550]].<ref>PMID:9927037</ref> Defects in MET are a cause of renal cell carcinoma papillary (RCCP) [MIM:[http://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>

-	~~Authors~~: ~~McTigue~~, M., ~~Wickersham~~, J., ~~Ryan~~, K.	+	==Function==
		+	[[http://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>

-	~~Description~~: X-~~ray Structure of c~~-~~Met~~ kinase ~~in complex with inhibitor 6-((6-(4-fluorophenyl)-(1~~,2,~~4)triazolo(4~~,~~3-b)(1,2,4)triazin-3-yl)methyl) quinoline~~.	+	==About this Structure==
		+	[[3zbx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZBX OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:023944843</ref><references group="xtra"/><references/>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: McTigue, M.]]
		+	[[Category: Ryan, K.]]
		+	[[Category: Wickersham, J.]]
		+	[[Category: Inhibitor]]
		+	[[Category: Transferase]]

OCA: Protected "3zbx" [edit=sysop:move=sysop]

OCA — Wed, 21 Nov 2012 08:53:30 GMT

Protected "3zbx" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:53, 21 November 2012

OCA: New page: '''Unreleased structure''' The entry 3zbx is ON HOLD until Paper Publication Authors: McTigue, M., Wickersham, J., Ryan, K. Description: X-ray Structure of c-Met kinase in complex with...

OCA — Wed, 21 Nov 2012 08:53:29 GMT

New page: '''Unreleased structure''' The entry 3zbx is ON HOLD until Paper Publication Authors: McTigue, M., Wickersham, J., Ryan, K. Description: X-ray Structure of c-Met kinase in complex with...

New page

'''Unreleased structure'''

The entry 3zbx is ON HOLD until Paper Publication

Authors: McTigue, M., Wickersham, J., Ryan, K.

Description: X-ray Structure of c-Met kinase in complex with inhibitor 6-((6-(4-fluorophenyl)-(1,2,4)triazolo(4,3-b)(1,2,4)triazin-3-yl)methyl) quinoline.