6squ - Revision history

OCA at 12:46, 24 January 2024

2024-01-24T12:46:10Z

← Older revision		Revision as of 12:46, 24 January 2024
Line 3:		Line 3:
	<StructureSection load='6squ' size='340' side='right'caption='[[6squ]], [[Resolution\|resolution]] 2.27Å' scene=''>		<StructureSection load='6squ' size='340' side='right'caption='[[6squ]], [[Resolution\|resolution]] 2.27Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[6squ]] is a 2 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=6SQU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SQU FirstGlance]. <br>		<table><tr><td colspan='2'>[[6squ]] is a 2 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=6SQU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SQU FirstGlance]. <br>
	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=D7I:5,5-(ethane~~-1,2~~-diylbis(oxy))bis(benzene-5,4,2,1,-tetrayl)hexakisphosphate'>D7I</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]] 2.27Å</td></tr>
	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>INPPL1, SHIP2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D7I:5,5-(ethane-1,2-diylbis(oxy))bis(benzene-5,4,2,1,-tetrayl)hexakisphosphate'>D7I</scene></td></tr>
	~~<tr~~ id~~='activity'><td class~~="~~sblockLbl~~"><~~b>Activity:</b></td><td class~~=~~"sblockDat"><span class~~=~~'plainlinks'>[https~~:~~//en.wikipedia.org/wiki/Phosphatidylinositol-3,4~~,5-~~trisphosphate_5~~-~~phosphatase Phosphatidylinositol~~-3,4,~~5-trisphosphate 5-phosphatase]~~, ~~with EC number [https://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=3.1.3.86 3.1.3.86]~~ </~~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=6squ FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6squ OCA], [https://pdbe.org/6squ PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6squ RCSB], [https://www.ebi.ac.uk/pdbsum/6squ PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6squ 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=6squ FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6squ OCA], [https://pdbe.org/6squ PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6squ RCSB], [https://www.ebi.ac.uk/pdbsum/6squ PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6squ ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[[https://www.uniprot.org/uniprot/SHIP2_HUMAN SHIP2_HUMAN]] Defects in INPPL1 may be a cause of susceptibility to type 2 diabetes mellitus non-insulin dependent (NIDDM) [MIM:[https://omim.org/entry/125853 125853]].<ref>PMID:12086927</ref> <ref>PMID:15687335</ref> Note=Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent.		[https://www.uniprot.org/uniprot/SHIP2_HUMAN SHIP2_HUMAN] Defects in INPPL1 may be a cause of susceptibility to type 2 diabetes mellitus non-insulin dependent (NIDDM) [MIM:[https://omim.org/entry/125853 125853].<ref>PMID:12086927</ref> <ref>PMID:15687335</ref> Note=Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent.
	== Function ==		== Function ==
	[[https://www.uniprot.org/uniprot/SHIP2_HUMAN SHIP2_HUMAN]] Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling. Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6.<ref>PMID:9660833</ref> <ref>PMID:11349134</ref> <ref>PMID:11739414</ref> <ref>PMID:12235291</ref> <ref>PMID:12676785</ref> <ref>PMID:12690104</ref> <ref>PMID:15668240</ref> <ref>PMID:17135240</ref>		[https://www.uniprot.org/uniprot/SHIP2_HUMAN SHIP2_HUMAN] Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling. Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6.<ref>PMID:9660833</ref> <ref>PMID:11349134</ref> <ref>PMID:11739414</ref> <ref>PMID:12235291</ref> <ref>PMID:12676785</ref> <ref>PMID:12690104</ref> <ref>PMID:15668240</ref> <ref>PMID:17135240</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 26:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Human~~]]		[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	~~[[Category: Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase]]~~		[[Category: Brearley CA]]
	[[Category: Brearley~~, C A~~]]		[[Category: Hemmings AM]]
	[[Category: Hemmings~~, A M~~]]		[[Category: Whitfield H]]
	[[Category: Whitfield, H]]
	~~[[Category: Hydrolase~~]]

OCA at 10:40, 28 July 2021

2021-07-28T10:40:18Z

← Older revision		Revision as of 10:40, 28 July 2021
Line 1:		Line 1:

	==Crystal structure of human SHIP2 catalytic domain in complex with 1,2,4 Dimer==		==Crystal structure of human SHIP2 catalytic domain in complex with 1,2,4 Dimer==
	<StructureSection load='6squ' size='340' side='right'caption='[[6squ]]' scene=''>		<StructureSection load='6squ' size='340' side='right'caption='[[6squ]], [[Resolution\|resolution]] 2.27Å' 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=6SQU OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=6SQU FirstGlance]. <br>		<table><tr><td colspan='2'>[[6squ]] is a 2 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=6SQU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SQU FirstGlance]. <br>
	</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=6squ FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6squ OCA], [~~http~~://pdbe.org/6squ PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6squ RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6squ PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6squ 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=D7I:5,5-(ethane-1,2-diylbis(oxy))bis(benzene-5,4,2,1,-tetrayl)hexakisphosphate'>D7I</scene></td></tr>
			<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">INPPL1, SHIP2 ([https://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'>[https://en.wikipedia.org/wiki/Phosphatidylinositol-3,4,5-trisphosphate_5-phosphatase Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.86 3.1.3.86] </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=6squ FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6squ OCA], [https://pdbe.org/6squ PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6squ RCSB], [https://www.ebi.ac.uk/pdbsum/6squ PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6squ ProSAT]</span></td></tr>
	</table>		</table>
			== Disease ==
			[[https://www.uniprot.org/uniprot/SHIP2_HUMAN SHIP2_HUMAN]] Defects in INPPL1 may be a cause of susceptibility to type 2 diabetes mellitus non-insulin dependent (NIDDM) [MIM:[https://omim.org/entry/125853 125853]].<ref>PMID:12086927</ref> <ref>PMID:15687335</ref> Note=Genetic variations in INPPL1 may be a cause of susceptibility to metabolic syndrome. Metabolic syndrome is characterized by diabetes, insulin resistance, hypertension, and hypertriglyceridemia is absent.
			== Function ==
			[[https://www.uniprot.org/uniprot/SHIP2_HUMAN SHIP2_HUMAN]] Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways. Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear. While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking. Confers resistance to dietary obesity. May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane. Part of a signaling pathway that regulates actin cytoskeleton remodeling. Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation. Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling. Regulates cell adhesion and cell spreading. Required for HGF-mediated lamellipodium formation, cell scattering and spreading. Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation. Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth. Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Involved in EGF signaling pathway. Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3. Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity. Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1. In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling. May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6.<ref>PMID:9660833</ref> <ref>PMID:11349134</ref> <ref>PMID:11739414</ref> <ref>PMID:12235291</ref> <ref>PMID:12676785</ref> <ref>PMID:12690104</ref> <ref>PMID:15668240</ref> <ref>PMID:17135240</ref>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			Src homology 2 domain-containing inositol phosphate phosphatase 2 (SHIP2) is one of the 10 human inositol phosphate 5-phosphatases. One of its physiological functions is dephosphorylation of phosphatidylinositol 3,4,5-trisphosphate, PtdIns(3,4,5)P3. It is therefore a therapeutic target for pathophysiologies dependent on PtdIns(3,4,5)P3 and PtdIns(3,4)P2. Therapeutic interventions are limited by the dearth of crystallographic data describing ligand/inhibitor binding. An active site-directed fluorescent probe facilitated screening of compound libraries for SHIP2 ligands. With two additional orthogonal assays, several ligands including galloflavin were identified as low micromolar Ki inhibitors. One ligand, an oxo-linked ethylene-bridged dimer of benzene 1,2,4-trisphosphate, was shown to be an uncompetitive inhibitor that binds to a regulatory site on the catalytic domain. We posit that binding of ligands to this site restrains L4 loop motions that are key to interdomain communications that accompany high catalytic activity with phosphoinositide substrate. This site may, therefore, be a future druggable target for medicinal chemistry.

			Allosteric Site on SHIP2 Identified Through Fluorescent Ligand Screening and Crystallography: A Potential New Target for Intervention.,Whitfield H, Hemmings AM, Mills SJ, Baker K, White G, Rushworth S, Riley AM, Potter BVL, Brearley CA J Med Chem. 2021 Apr 8;64(7):3813-3826. doi: 10.1021/acs.jmedchem.0c01944. Epub, 2021 Mar 16. PMID:33724834<ref>PMID:33724834</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 6squ" style="background-color:#fffaf0;"></div>
			== References ==
			<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Human]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Brearley CA]]		[[Category: Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase]]
	[[Category: Hemmings AM]]		[[Category: Brearley, C A]]
	[[Category: Whitfield H]]		[[Category: Hemmings, A M]]
			[[Category: Whitfield, H]]
			[[Category: Hydrolase]]

OCA at 05:47, 20 January 2021

2021-01-20T05:47:37Z

← Older revision		Revision as of 05:47, 20 January 2021
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The entry~~ 6squ is ~~ON HOLD until Paper Publication~~		==Crystal structure of human SHIP2 catalytic domain in complex with 1,2,4 Dimer==
			<StructureSection load='6squ' size='340' side='right'caption='[[6squ]]' scene=''>
	~~Authors~~:		== Structural highlights ==
			<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SQU OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6SQU FirstGlance]. <br>
	~~Description~~:		</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=6squ FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6squ OCA], [http://pdbe.org/6squ PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6squ RCSB], [http://www.ebi.ac.uk/pdbsum/6squ PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6squ ProSAT]</span></td></tr>
	[[Category: ~~Unreleased Structures~~]]		</table>
			__TOC__
			</StructureSection>
			[[Category: Large Structures]]
			[[Category: Brearley CA]]
			[[Category: Hemmings AM]]
			[[Category: Whitfield H]]

OCA: Protected "6squ" [edit=sysop:move=sysop]

2019-10-02T07:37:14Z

Protected "6squ" [edit=sysop:move=sysop]

← Older revision	Revision as of 07:37, 2 October 2019
(No difference)

OCA: New page: '''Unreleased structure''' The entry 6squ is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

2019-10-02T07:37:13Z

New page: '''Unreleased structure''' The entry 6squ is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 6squ is ON HOLD until Paper Publication

Authors:

Description:
[[Category: Unreleased Structures]]