4qq5 - Revision history

OCA at 17:35, 20 September 2023

2023-09-20T17:35:18Z

←Older revision		Revision as of 17:35, 20 September 2023
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	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4qq5]] 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=4QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QQ5 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4qq5]] 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=4QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QQ5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=37O:N-(4-{[3-(3,5-DIMETHOXYPHENYL)-7-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-2-OXO-3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1(2H)-YL]METHYL}PHENYL)PROPANAMIDE'>37O</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]] 2.203Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=37O:N-(4-{[3-(3,5-DIMETHOXYPHENYL)-7-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-2-OXO-3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1(2H)-YL]METHYL}PHENYL)PROPANAMIDE'>37O</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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [https://pdbe.org/4qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/4qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qq5 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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [https://pdbe.org/4qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/4qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qq5 ProSAT]</span></td></tr>
	</table>		</table>

OCA at 13:46, 22 February 2023

2023-02-22T13:46:45Z

←Older revision		Revision as of 13:46, 22 February 2023
Line 3:		Line 3:
	<StructureSection load='4qq5' size='340' side='right'caption='[[4qq5]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='4qq5' size='340' side='right'caption='[[4qq5]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4qq5]] 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=4QQ5 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4QQ5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4qq5]] 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=4QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4QQ5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=37O:N-(4-{[3-(3,5-DIMETHOXYPHENYL)-7-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-2-OXO-3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1(2H)-YL]METHYL}PHENYL)PROPANAMIDE'>37O</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=37O:N-(4-{[3-(3,5-DIMETHOXYPHENYL)-7-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-2-OXO-3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1(2H)-YL]METHYL}PHENYL)PROPANAMIDE'>37O</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qqc\|4qqc]], [[4qqj\|4qqj]], [[4qqt\|4qqt]], [[4qrc\|4qrc]]</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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [https://pdbe.org/4qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/4qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4qq5 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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [~~http~~://pdbe.org/4qq5 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4qq5 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4qq5 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 08:36, 24 April 2019

2019-04-24T08:36:38Z

←Older revision		Revision as of 08:36, 24 April 2019
Line 1:		Line 1:

	==Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex With FIIN-2, 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-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR Kinase Gate-Keeper Mutations==
-	<StructureSection load='4qq5' size='340' side='right' caption='[[4qq5]], [[Resolution\|resolution]] 2.20Å' scene=''>	+	<StructureSection load='4qq5' size='340' side='right'caption='[[4qq5]], [[Resolution\|resolution]] 2.20Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4qq5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QQ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QQ5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4qq5]] 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=4QQ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QQ5 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=37O:N-(4-{[3-(3,5-DIMETHOXYPHENYL)-7-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-2-OXO-3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1(2H)-YL]METHYL}PHENYL)PROPANAMIDE'>37O</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=37O:N-(4-{[3-(3,5-DIMETHOXYPHENYL)-7-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-2-OXO-3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1(2H)-YL]METHYL}PHENYL)PROPANAMIDE'>37O</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qqc\|4qqc]], [[4qqj\|4qqj]], [[4qqt\|4qqt]], [[4qrc\|4qrc]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qqc\|4qqc]], [[4qqj\|4qqj]], [[4qqt\|4qqt]], [[4qrc\|4qrc]]</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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [http://pdbe.org/4qq5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [http://www.ebi.ac.uk/pdbsum/4qq5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qq5 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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [http://pdbe.org/4qq5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [http://www.ebi.ac.uk/pdbsum/4qq5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qq5 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 08:07, 11 August 2016

2016-08-11T08:07:43Z

←Older revision		Revision as of 08:07, 11 August 2016
Line 1:		Line 1:
		+
	==Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V550L Gate-Keeper Mutation in Complex With FIIN-2, 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-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR Kinase Gate-Keeper Mutations==
	<StructureSection load='4qq5' size='340' side='right' caption='[[4qq5]], [[Resolution\|resolution]] 2.20Å' scene=''>		<StructureSection load='4qq5' size='340' side='right' caption='[[4qq5]], [[Resolution\|resolution]] 2.20Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qqc\|4qqc]], [[4qqj\|4qqj]], [[4qqt\|4qqt]], [[4qrc\|4qrc]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qqc\|4qqc]], [[4qqj\|4qqj]], [[4qqt\|4qqt]], [[4qrc\|4qrc]]</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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [http://www.ebi.ac.uk/pdbsum/4qq5 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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [http://pdbe.org/4qq5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [http://www.ebi.ac.uk/pdbsum/4qq5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qq5 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 4qq5" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Fibroblast growth factor receptor\|Fibroblast growth factor receptor]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 22:44, 24 December 2014

2014-12-24T22:44:24Z

←Older revision		Revision as of 22:44, 24 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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [http://www.ebi.ac.uk/pdbsum/4qq5 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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [http://www.ebi.ac.uk/pdbsum/4qq5 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 ==
Line 21:		Line 23:
	</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 11:12, 29 October 2014

2014-10-29T11:12:50Z

←Older revision		Revision as of 11:12, 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-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR Kinase Gate-Keeper Mutations==
		+	<StructureSection load='4qq5' size='340' side='right' caption='[[4qq5]], [[Resolution\|resolution]] 2.20Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4qq5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QQ5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QQ5 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=37O:N-(4-{[3-(3,5-DIMETHOXYPHENYL)-7-{[4-(4-METHYLPIPERAZIN-1-YL)PHENYL]AMINO}-2-OXO-3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1(2H)-YL]METHYL}PHENYL)PROPANAMIDE'>37O</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4qqc\|4qqc]], [[4qqj\|4qqj]], [[4qqt\|4qqt]], [[4qrc\|4qrc]]</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=4qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qq5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qq5 RCSB], [http://www.ebi.ac.uk/pdbsum/4qq5 PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Drug-resistance acquisition through kinase gate-keeper mutations is a major hurdle in the clinic. Here, we determined the first crystal structures of the human FGFR4 kinase domain (FGFR4K) alone and complexed with ponatinib, a promiscuous type-2 (DFG-out) kinase inhibitor, and an oncogenic FGFR4K harboring the V550L gate-keeper mutation bound to FIIN-2, a new type-1 irreversible inhibitor. Remarkably, like ponatinib, FIIN-2 also binds in the DFG-out mode despite lacking a functional group necessary to occupy the pocket vacated upon the DFG-out flip. Structural analysis reveals that the covalent bond between FIIN-2 and a cysteine, uniquely present in the glycine-rich loop of FGFR kinases, facilitates the DFG-out conformation, which together with the internal flexibility of FIIN-2 enables FIIN-2 to avoid the steric clash with the gate-keeper mutation that causes the ponatinib resistance. The structural data provide a blueprint for the development of next generation anticancer inhibitors through combining the salient inhibitory mechanisms of ponatinib and FIIN-2.

-	~~The entry 4qq5 is ON HOLD until Paper Publication~~	+	DFG-out Mode of Inhibition by an Irreversible Type-1 Inhibitor Capable of Overcoming Gate-Keeper Mutations in FGF Receptors.,Huang Z, Tan L, Wang H, Liu Y, Blais S, Deng J, Neubert TA, Gray NS, Li X, Mohammadi M ACS Chem Biol. 2014 Oct 27. PMID:25317566<ref>PMID:25317566</ref>

-	~~Authors~~: Huang, Z., Mohammadi, M.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~: ~~Crystal Structure of FGF Receptor (FGFR) 4~~ Kinase ~~Harboring the V550L Gate-Keeper Mutation in Complex With FIIN-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR Kinase Gate~~-~~Keeper Mutations~~	+	== References ==
		+	<references/>
		+	__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 09:21, 20 October 2014

2014-10-20T09:21:51Z

←Older revision		Revision as of 09:21, 20 October 2014
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	Authors: Huang, Z., Mohammadi, M.		Authors: Huang, Z., Mohammadi, M.

-	Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the ~~V555L~~ Gate-Keeper Mutation in Complex ~~with~~ FIIN-2, 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-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR Kinase Gate-Keeper Mutations

OCA at 08:13, 24 September 2014

2014-09-24T08:13:58Z

←Older revision		Revision as of 08:13, 24 September 2014
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4qq5 is ON HOLD	+	The entry 4qq5 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 V555L Gate-Keeper Mutation in Complex with FIIN-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations		Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V555L Gate-Keeper Mutation in Complex with FIIN-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations

OCA: Protected "4qq5" [edit=sysop:move=sysop]

2014-07-02T07:28:45Z

Protected "4qq5" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:28, 2 July 2014

OCA: New page: '''Unreleased structure''' The entry 4qq5 is ON HOLD Authors: Huang, Z., Mohammadi, M. Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V555L Gate-Keeper Mu...

2014-07-02T07:28:44Z

New page: '''Unreleased structure''' The entry 4qq5 is ON HOLD Authors: Huang, Z., Mohammadi, M. Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V555L Gate-Keeper Mu...

New page

'''Unreleased structure'''

The entry 4qq5 is ON HOLD

Authors: Huang, Z., Mohammadi, M.

Description: Crystal Structure of FGF Receptor (FGFR) 4 Kinase Harboring the V555L Gate-Keeper Mutation in Complex with FIIN-2, an Irreversible Tyrosine Kinase Inhibitor Capable of Overcoming FGFR kinase Gate-Keeper Mutations