4r6v - Revision history

OCA at 17:45, 20 September 2023

2023-09-20T17:45:07Z

←Older revision		Revision as of 17:45, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4r6v]] 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=4R6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R6V FirstGlance]. <br>		<table><tr><td colspan='2'>[[4r6v]] 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=4R6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R6V FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.353Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [https://pdbe.org/4r6v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [https://www.ebi.ac.uk/pdbsum/4r6v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r6v 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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [https://pdbe.org/4r6v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [https://www.ebi.ac.uk/pdbsum/4r6v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r6v ProSAT]</span></td></tr>
	</table>		</table>

OCA at 06:42, 2 March 2023

2023-03-02T06:42:33Z

←Older revision		Revision as of 06:42, 2 March 2023
Line 3:		Line 3:
	<StructureSection load='4r6v' size='340' side='right'caption='[[4r6v]], [[Resolution\|resolution]] 2.35Å' scene=''>		<StructureSection load='4r6v' size='340' side='right'caption='[[4r6v]], [[Resolution\|resolution]] 2.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4r6v]] 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=4R6V OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4R6V FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4r6v]] 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=4R6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R6V FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qq5\|4qq5]], [[4qqc\|4qqc]], [[4qqt\|4qqt]], [[4qrc\|4qrc]], [[4qqj\|4qqj]]</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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [https://pdbe.org/4r6v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [https://www.ebi.ac.uk/pdbsum/4r6v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r6v ProSAT]</span></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">FGFR4, JTK2, TKF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [~~http~~://pdbe.org/4r6v PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4r6v PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4r6v ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/FGFR4_HUMAN FGFR4_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.<ref>PMID:7680645</ref> <ref>PMID:7518429</ref> <ref>PMID:8663044</ref> <ref>PMID:11433297</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:18670643</ref> <ref>PMID:20683963</ref> <ref>PMID:20018895</ref> <ref>PMID:20798051</ref> <ref>PMID:21653700</ref> <ref>PMID:20876804</ref>	+	[https://www.uniprot.org/uniprot/FGFR4_HUMAN FGFR4_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.<ref>PMID:7680645</ref> <ref>PMID:7518429</ref> <ref>PMID:8663044</ref> <ref>PMID:11433297</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:18670643</ref> <ref>PMID:20683963</ref> <ref>PMID:20018895</ref> <ref>PMID:20798051</ref> <ref>PMID:21653700</ref> <ref>PMID:20876804</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 20:

	==See Also==		==See Also==
-	*[[Fibroblast growth factor receptor\|Fibroblast growth factor receptor]]	+	*[[Fibroblast growth factor receptor 3D receptor\|Fibroblast growth factor receptor 3D receptor]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Huang Z]]
-	[[Category: Huang, Z]]	+	[[Category: Mohammadi M]]
-	[[Category: Mohammadi, M]]	+
-	~~[[Category: Cell signaling]]~~	+
-	~~[[Category: Kinase domain fold]]~~	+
-	~~[[Category: Phosphotransferase]]~~	+
-	~~[[Category: Plasmamembrane]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 09:42, 1 May 2019

2019-05-01T09:42:28Z

←Older revision		Revision as of 09:42, 1 May 2019
Line 1:		Line 1:

	==Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations==		==Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations==
-	<StructureSection load='4r6v' size='340' side='right' caption='[[4r6v]], [[Resolution\|resolution]] 2.35Å' scene=''>	+	<StructureSection load='4r6v' size='340' side='right'caption='[[4r6v]], [[Resolution\|resolution]] 2.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4r6v]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R6V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R6V FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4r6v]] 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=4R6V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R6V FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qq5\|4qq5]], [[4qqc\|4qqc]], [[4qqt\|4qqt]], [[4qrc\|4qrc]], [[4qqj\|4qqj]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qq5\|4qq5]], [[4qqc\|4qqc]], [[4qqt\|4qqt]], [[4qrc\|4qrc]], [[4qqj\|4qqj]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">FGFR4, JTK2, TKF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://pdbe.org/4r6v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r6v ProSAT]</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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://pdbe.org/4r6v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r6v ProSAT]</span></td></tr>
Line 27:		Line 28:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Huang, Z]]		[[Category: Huang, Z]]

OCA at 19:08, 4 August 2016

2016-08-04T19:08:57Z

←Older revision		Revision as of 19:08, 4 August 2016
Line 1:		Line 1:
		+
	==Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations==		==Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations==
	<StructureSection load='4r6v' size='340' side='right' caption='[[4r6v]], [[Resolution\|resolution]] 2.35Å' scene=''>		<StructureSection load='4r6v' size='340' side='right' caption='[[4r6v]], [[Resolution\|resolution]] 2.35Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qq5\|4qq5]], [[4qqc\|4qqc]], [[4qqt\|4qqt]], [[4qrc\|4qrc]], [[4qqj\|4qqj]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qq5\|4qq5]], [[4qqc\|4qqc]], [[4qqt\|4qqt]], [[4qrc\|4qrc]], [[4qqj\|4qqj]]</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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v 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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://pdbe.org/4r6v PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r6v ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	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 4r6v" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Fibroblast growth factor receptor\|Fibroblast growth factor receptor]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:15, 25 December 2014

2014-12-25T12:15:41Z

←Older revision		Revision as of 12:15, 25 December 2014
Line 8:		Line 8:
	<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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v 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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/FGFR4_HUMAN FGFR4_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.<ref>PMID:7680645</ref> <ref>PMID:7518429</ref> <ref>PMID:8663044</ref> <ref>PMID:11433297</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:18670643</ref> <ref>PMID:20683963</ref> <ref>PMID:20018895</ref> <ref>PMID:20798051</ref> <ref>PMID:21653700</ref> <ref>PMID:20876804</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==

OCA at 06:04, 26 November 2014

2014-11-26T06:04:11Z

←Older revision		Revision as of 06:04, 26 November 2014
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	<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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v 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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v PDBsum]</span></td></tr>
	</table>		</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.
		+
		+	Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.,Tan L, Wang J, Tanizaki J, Huang Z, Aref AR, Rusan M, Zhu SJ, Zhang Y, Ercan D, Liao RG, Capelletti M, Zhou W, Hur W, Kim N, Sim T, Gaudet S, Barbie DA, Yeh JR, Yun CH, Hammerman PS, Mohammadi M, Janne PA, Gray NS Proc Natl Acad Sci U S A. 2014 Oct 27. pii: 201403438. PMID:25349422<ref>PMID:25349422</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Huang, Z.]]	+	[[Category: Huang, Z]]
-	[[Category: Mohammadi, M.]]	+	[[Category: Mohammadi, M]]
	[[Category: Cell signaling]]		[[Category: Cell signaling]]
	[[Category: Kinase domain fold]]		[[Category: Kinase domain fold]]

OCA at 11:31, 29 October 2014

2014-10-29T11:31:00Z

←Older revision		Revision as of 11:31, 29 October 2014
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-	~~'''Unreleased structure'''~~	+	==Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations==
-		+	<StructureSection load='4r6v' size='340' side='right' caption='[[4r6v]], [[Resolution\|resolution]] 2.35Å' scene=''>
-	~~The entry 4r6v is ON HOLD until Paper Publication~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>[[4r6v]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R6V OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R6V FirstGlance]. <br>
-	~~Authors: Huang, Z., Mohammadi, M.~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FI3:N-[4-({[(2,6-DICHLORO-3,5-DIMETHOXYPHENYL)CARBAMOYL](6-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}PYRIMIDIN-4-YL)AMINO}METHYL)PHENYL]PROPANAMIDE'>FI3</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qq5\|4qq5]], [[4qqc\|4qqc]], [[4qqt\|4qqt]], [[4qrc\|4qrc]], [[4qqj\|4qqj]]</td></tr>
-	~~Description:~~ Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations	+	<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=4r6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r6v OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r6v RCSB], [http://www.ebi.ac.uk/pdbsum/4r6v PDBsum]</span></td></tr>
		+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Huang, Z.]]
		+	[[Category: Mohammadi, M.]]
		+	[[Category: Cell signaling]]
		+	[[Category: Kinase domain fold]]
		+	[[Category: Phosphotransferase]]
		+	[[Category: Plasmamembrane]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 09:24, 20 October 2014

2014-10-20T09:24:57Z

←Older revision		Revision as of 09:24, 20 October 2014
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4r6v is ON HOLD	+	The entry 4r6v is ON HOLD until Paper Publication

	Authors: Huang, Z., Mohammadi, M.		Authors: Huang, Z., Mohammadi, M.

	Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations		Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations

OCA: Protected "4r6v" [edit=sysop:move=sysop]

2014-09-04T04:17:47Z

Protected "4r6v" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:17, 4 September 2014

OCA: New page: '''Unreleased structure''' The entry 4r6v is ON HOLD Authors: Huang, Z., Mohammadi, M. Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mu...

2014-09-04T04:17:45Z

New page: '''Unreleased structure''' The entry 4r6v is ON HOLD Authors: Huang, Z., Mohammadi, M. Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mu...

New page

'''Unreleased structure'''

The entry 4r6v is ON HOLD

Authors: Huang, Z., Mohammadi, M.

Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex with FIIN-3, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations