5wg5 - Revision history

OCA at 14:12, 4 October 2023

2023-10-04T14:12:18Z

←Older revision		Revision as of 14:12, 4 October 2023
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	<StructureSection load='5wg5' size='340' side='right'caption='[[5wg5]], [[Resolution\|resolution]] 3.10Å' scene=''>		<StructureSection load='5wg5' size='340' side='right'caption='[[5wg5]], [[Resolution\|resolution]] 3.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wg5]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WG5 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5WG5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wg5]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WG5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WG5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZSO:5-{[(3S,4R)-4-(4-fluorophenyl)piperidin-3-yl]methoxy}-2H-indazole'>ZSO</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]] 3.1Å</td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Beta-adrenergic-receptor]_kinase [Beta-adrenergic-receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.15 2.7.11.15] </span></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZSO:5-{[(3S,4R)-4-(4-fluorophenyl)piperidin-3-yl]methoxy}-2H-indazole'>ZSO</scene></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5wg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wg5 OCA], [~~http~~://pdbe.org/5wg5 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5wg5 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5wg5 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5wg5 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=5wg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wg5 OCA], [https://pdbe.org/5wg5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wg5 RCSB], [https://www.ebi.ac.uk/pdbsum/5wg5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wg5 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/ARBK1_HUMAN ARBK1_HUMAN]] Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.<ref>PMID:19306925</ref> [[http://www.uniprot.org/uniprot/GBG2_BOVIN GBG2_BOVIN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. [[http://www.uniprot.org/uniprot/GBB1_BOVIN GBB1_BOVIN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.	+	[https://www.uniprot.org/uniprot/ARBK1_HUMAN ARBK1_HUMAN] Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.<ref>PMID:19306925</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Bos taurus]]
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Bouley, R]]	+	[[Category: Bouley R]]
-	[[Category: Tesmer~~, J J.G]]~~	+	[[Category: Tesmer JJG]]
-	~~[[Category: Transferase~~]]	+

OCA at 08:52, 30 September 2020

2020-09-30T08:52:29Z

←Older revision		Revision as of 08:52, 30 September 2020
Line 1:		Line 1:

	==Human GRK2 in complex with Gbetagamma subunits and CCG224061==		==Human GRK2 in complex with Gbetagamma subunits and CCG224061==
-	<StructureSection load='5wg5' size='340' side='right' caption='[[5wg5]], [[Resolution\|resolution]] 3.10Å' scene=''>	+	<StructureSection load='5wg5' size='340' side='right'caption='[[5wg5]], [[Resolution\|resolution]] 3.10Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wg5]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WG5 OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5WG5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wg5]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WG5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5WG5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZSO:5-{[(3S,4R)-4-(4-fluorophenyl)piperidin-3-yl]methoxy}-2H-indazole'>ZSO</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZSO:5-{[(3S,4R)-4-(4-fluorophenyl)piperidin-3-yl]methoxy}-2H-indazole'>ZSO</scene></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Beta-adrenergic-receptor]_kinase [Beta-adrenergic-receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.15 2.7.11.15] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Beta-adrenergic-receptor]_kinase [Beta-adrenergic-receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.15 2.7.11.15] </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=5wg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wg5 OCA], [http://pdbe.org/5wg5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wg5 RCSB], [http://www.ebi.ac.uk/pdbsum/5wg5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wg5 ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5wg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wg5 OCA], [http://pdbe.org/5wg5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wg5 RCSB], [http://www.ebi.ac.uk/pdbsum/5wg5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wg5 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5wg5" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5wg5" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Beta adrenergic receptor kinase 3D structures\|Beta adrenergic receptor kinase 3D structures]]
		+	*[[Transducin 3D structures\|Transducin 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Bouley, R]]		[[Category: Bouley, R]]
	[[Category: Tesmer, J J.G]]		[[Category: Tesmer, J J.G]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 08:29, 27 December 2017

2017-12-27T08:29:16Z

←Older revision		Revision as of 08:29, 27 December 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5wg5 is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Human GRK2 in complex with Gbetagamma subunits and CCG224061==
		+	<StructureSection load='5wg5' size='340' side='right' caption='[[5wg5]], [[Resolution\|resolution]] 3.10Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5wg5]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WG5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WG5 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZSO:5-{[(3S,4R)-4-(4-fluorophenyl)piperidin-3-yl]methoxy}-2H-indazole'>ZSO</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Beta-adrenergic-receptor]_kinase [Beta-adrenergic-receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.15 2.7.11.15] </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=5wg5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wg5 OCA], [http://pdbe.org/5wg5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wg5 RCSB], [http://www.ebi.ac.uk/pdbsum/5wg5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wg5 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/ARBK1_HUMAN ARBK1_HUMAN]] Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.<ref>PMID:19306925</ref> [[http://www.uniprot.org/uniprot/GBG2_BOVIN GBG2_BOVIN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. [[http://www.uniprot.org/uniprot/GBB1_BOVIN GBB1_BOVIN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	G protein-coupled receptor kinases (GRKs) phosphorylate activated receptors to promote arrestin binding, decoupling from heterotrimeric G proteins, and internalization. GRK2 and GRK5 are overexpressed in the failing heart and thus have become therapeutic targets. Previously, we discovered two classes of GRK2-selective inhibitors, one stemming from GSK180736A, a Rho-associated coiled-coil containing kinase 1 (ROCK1) inhibitor, the other from paroxetine, a selective serotonin-reuptake inhibitor. These two classes of compounds bind to the GRK2 active site in a similar configuration but contain different hinge-binding "warheads": indazole and benzodioxole, respectively. We surmised from our prior studies that an indazole would be the stronger hinge binder and would impart increased potency when substituted for benzodioxole in paroxetine derivatives. To test this hypothesis, we synthesized a series of hybrid compounds that allowed us to compare the effects of inhibitors that differ only in the identity of the warhead. The indazole-paroxetine analogs were indeed more potent than their respective benzodioxole derivatives but lost selectivity. To investigate how these two warheads dictate selectivity, we determined the crystal structures of three of the indazole hybrid compounds (CCG224061, CCG257284, and CCG258748) in complex with GRK2-Gbetagamma Comparison of these structures with those of analogous benzodioxole-containing complexes confirmed that the indazole-paroxetine hybrids form stronger interactions with the hinge of the kinase but also stabilize a distinct conformation of the kinase domain of GRK2 compared with previous complexes with paroxetine analogs. This conformation is analogous to one that can be assumed by GRK5, at least partially explaining the loss in selectivity.

-	~~Authors~~:	+	Structural Determinants Influencing the Potency and Selectivity of Indazole-Paroxetine Hybrid G Protein-Coupled Receptor Kinase 2 Inhibitors.,Bouley R, Waldschmidt HV, Cato MC, Cannavo A, Song J, Cheung JY, Yao XQ, Koch WJ, Larsen SD, Tesmer JJG Mol Pharmacol. 2017 Dec;92(6):707-717. doi: 10.1124/mol.117.110130. Epub 2017 Oct, 25. PMID:29070696<ref>PMID:29070696</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5wg5" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Bouley, R]]
		+	[[Category: Tesmer, J J.G]]
		+	[[Category: Transferase]]

OCA: Protected "5wg5" [edit=sysop:move=sysop]

2017-09-27T14:47:52Z

Protected "5wg5" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:47, 27 September 2017

OCA: New page: '''Unreleased structure''' The entry 5wg5 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

2017-09-27T14:47:49Z

New page: '''Unreleased structure''' The entry 5wg5 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 5wg5 is ON HOLD until Paper Publication

Authors:

Description:
[[Category: Unreleased Structures]]