7wcx - Revision history

OCA at 17:39, 29 November 2023

OCA — Wed, 29 Nov 2023 17:39:33 GMT

←Older revision		Revision as of 17:39, 29 November 2023
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	<StructureSection load='7wcx' size='340' side='right'caption='[[7wcx]], [[Resolution\|resolution]] 2.17Å' scene=''>		<StructureSection load='7wcx' size='340' side='right'caption='[[7wcx]], [[Resolution\|resolution]] 2.17Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7wcx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WCX FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7wcx]] 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=7WCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WCX FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=90F:~{N}-[2-[[5-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1~{H}-indazol-3-yl]amino]-3-fluoranyl-5-(4-morpholin-4-ylpiperidin-1-yl)phenyl]propanamide'>90F</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]] 2.175Å</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=90F:~{N}-[2-[[5-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1~{H}-indazol-3-yl]amino]-3-fluoranyl-5-(4-morpholin-4-ylpiperidin-1-yl)phenyl]propanamide'>90F</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=7wcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wcx OCA], [https://pdbe.org/7wcx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wcx RCSB], [https://www.ebi.ac.uk/pdbsum/7wcx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wcx 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=7wcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wcx OCA], [https://pdbe.org/7wcx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wcx RCSB], [https://www.ebi.ac.uk/pdbsum/7wcx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wcx ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[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>	+	[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 19:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 7wcx" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7wcx" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Fibroblast growth factor receptor 3D receptor\|Fibroblast growth factor receptor 3D receptor]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Receptor protein-tyrosine kinase]]~~	+	[[Category: Chen XJ]]
-	[[Category: Chen~~, X J~~]]	+	[[Category: Chen YH]]
-	[[Category: Chen~~, Y H~~]]	+	[[Category: Dai SY]]
-	[[Category: Dai~~, S Y~~]]	+	[[Category: Lin QM]]
-	[[Category: Lin~~, Q M]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Structural protein]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 10:40, 6 April 2022

OCA — Wed, 06 Apr 2022 10:40:09 GMT

←Older revision		Revision as of 10:40, 6 April 2022
Line 1:		Line 1:

	==Crystal structure of FGFR4(V550M) kinase domain with 7v==		==Crystal structure of FGFR4(V550M) kinase domain with 7v==
-	<StructureSection load='7wcx' size='340' side='right'caption='[[7wcx]]' scene=''>	+	<StructureSection load='7wcx' size='340' side='right'caption='[[7wcx]], [[Resolution\|resolution]] 2.17Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WCX FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7wcx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WCX FirstGlance]. <br>
-	</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=7wcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wcx OCA], [https://pdbe.org/7wcx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wcx RCSB], [https://www.ebi.ac.uk/pdbsum/7wcx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wcx ProSAT]</span></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=90F:~{N}-[2-[[5-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1~{H}-indazol-3-yl]amino]-3-fluoranyl-5-(4-morpholin-4-ylpiperidin-1-yl)phenyl]propanamide'>90F</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=7wcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wcx OCA], [https://pdbe.org/7wcx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wcx RCSB], [https://www.ebi.ac.uk/pdbsum/7wcx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wcx ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[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;">
		+	== Publication Abstract from PubMed ==
		+	Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. One representative compound (7v) exhibited excellent potency against FGFR4, FGFR4(V550L), and FGFR4(V550M) with nanomolar activity in both the biochemical and cellular assays while sparing FGFR1/2/3. While compound 7v demonstrated modest in vivo antitumor efficacy in nude mice bearing the Huh-7 xenograft model consistent with its unfavorable pharmacokinetic properties, it provides a promising new starting point for future drug discovery combating FGFR4 gatekeeper mediated resistance in HCC patients.
		+
		+	Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.,Shao M, Chen X, Yang F, Song X, Zhou Y, Lin Q, Fu Y, Ortega R, Lin X, Tu Z, Patterson AV, Smaill JB, Chen Y, Lu X J Med Chem. 2022 Mar 24;65(6):5113-5133. doi: 10.1021/acs.jmedchem.2c00096. Epub , 2022 Mar 10. PMID:35271262<ref>PMID:35271262</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7wcx" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Chen XJ]]	+	[[Category: Receptor protein-tyrosine kinase]]
-	[[Category: Chen YH]]	+	[[Category: Chen, X J]]
-	[[Category: Dai SY]]	+	[[Category: Chen, Y H]]
-	[[Category: Lin QM]]	+	[[Category: Dai, S Y]]
		+	[[Category: Lin, Q M]]
		+	[[Category: Inhibitor]]
		+	[[Category: Kinase]]
		+	[[Category: Structural protein]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA at 10:49, 30 March 2022

OCA — Wed, 30 Mar 2022 10:49:22 GMT

←Older revision		Revision as of 10:49, 30 March 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 7wcx is ~~ON HOLD until Paper Publication~~	+	==Crystal structure of FGFR4(V550M) kinase domain with 7v==
-		+	<StructureSection load='7wcx' size='340' side='right'caption='[[7wcx]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WCX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WCX FirstGlance]. <br>
-	~~Description~~:	+	</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=7wcx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wcx OCA], [https://pdbe.org/7wcx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wcx RCSB], [https://www.ebi.ac.uk/pdbsum/7wcx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wcx ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Chen XJ]]
		+	[[Category: Chen YH]]
		+	[[Category: Dai SY]]
		+	[[Category: Lin QM]]

OCA at 05:45, 2 February 2022

OCA — Wed, 02 Feb 2022 05:45:08 GMT

←Older revision		Revision as of 05:45, 2 February 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7wcx is ON HOLD	+	The entry 7wcx is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7wcx" [edit=sysop:move=sysop]

OCA — Wed, 29 Dec 2021 12:39:49 GMT

Protected "7wcx" [edit=sysop:move=sysop]

←Older revision

Revision as of 12:39, 29 December 2021

OCA: New page: '''Unreleased structure''' The entry 7wcx is ON HOLD Authors: Description: Category: Unreleased Structures

OCA — Wed, 29 Dec 2021 12:39:48 GMT

New page: '''Unreleased structure''' The entry 7wcx is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7wcx is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]