4hvb - Revision history

OCA at 11:44, 1 March 2024

2024-03-01T11:44:57Z

← Older revision		Revision as of 11:44, 1 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4hvb]] 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=4HVB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HVB FirstGlance]. <br>		<table><tr><td colspan='2'>[[4hvb]] 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=4HVB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HVB FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</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]] 2.35Å</td></tr>
			<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</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=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [https://pdbe.org/4hvb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [https://www.ebi.ac.uk/pdbsum/4hvb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hvb 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=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [https://pdbe.org/4hvb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [https://www.ebi.ac.uk/pdbsum/4hvb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hvb ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>		[https://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.

	Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.,Cheng H, Li C, Bailey S, Baxi SM, Goulet L, Guo L, Hoffman J, Jiang Y, Johnson TO, Johnson TW, Knighton DR, Li J, Liu KK, Liu Z, Marx MA, Walls M, Wells PA, Yin MJ, Zhu J, Zientek M ACS Med Chem Lett. 2012 Nov 7;4(1):91-7. doi: 10.1021/ml300309h. eCollection 2013, Jan 10. PMID:24900568<ref>PMID:24900568</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 4hvb" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==

OCA at 08:18, 9 November 2022

2022-11-09T08:18:08Z

← Older revision		Revision as of 08:18, 9 November 2022
Line 1:		Line 1:

	==Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064==		==Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064==
	<StructureSection load='4hvb' size='340' side='right' caption='[[4hvb]], [[Resolution\|resolution]] 2.35Å' scene=''>		<StructureSection load='4hvb' size='340' side='right'caption='[[4hvb]], [[Resolution\|resolution]] 2.35Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4hvb]] 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=4HVB OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4HVB FirstGlance]. <br>		<table><tr><td colspan='2'>[[4hvb]] 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=4HVB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HVB FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</scene>~~</td></tr>~~		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</scene></td></tr>
	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</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=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [https://pdbe.org/4hvb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [https://www.ebi.ac.uk/pdbsum/4hvb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hvb 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=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [~~http~~://pdbe.org/4hvb PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4hvb PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4hvb ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[~~[http~~://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>		[https://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 21:		Line 20:

	==See Also==		==See Also==
	*[[Phosphoinositide 3-~~Kinases~~\|Phosphoinositide 3-~~Kinases~~]]		*[[Phosphoinositide 3-kinase 3D structures\|Phosphoinositide 3-kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: ~~Human~~]]		[[Category: Homo sapiens]]
	[[Category: ~~Cheng, H~~]]		[[Category: Large Structures]]
	[[Category: ~~Knighton, D R~~]]		[[Category: Cheng H]]
	[[Category: ~~Kinase]]~~		[[Category: Knighton DR]]
	~~[[Category: Lipid kinase]]~~
	~~[[Category: Phosphoinositide kinase]]~~
	~~[[Category: Transferase-transferase inhibitor complex~~]]

OCA at 23:29, 4 August 2016

2016-08-04T23:29:54Z

← Older revision		Revision as of 23:29, 4 August 2016
Line 1:		Line 1:

	==Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064==		==Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064==
	<StructureSection load='4hvb' size='340' side='right' caption='[[4hvb]], [[Resolution\|resolution]] 2.35Å' scene=''>		<StructureSection load='4hvb' size='340' side='right' caption='[[4hvb]], [[Resolution\|resolution]] 2.35Å' scene=''>
Line 5:		Line 6:
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</scene></td></tr>
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [http://www.ebi.ac.uk/pdbsum/4hvb 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=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [http://pdbe.org/4hvb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [http://www.ebi.ac.uk/pdbsum/4hvb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4hvb ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 17:		Line 18:
	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 4hvb" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 14:00, 25 December 2014

2014-12-25T14:00:24Z

← Older revision		Revision as of 14:00, 25 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4hvb]] 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=4HVB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HVB FirstGlance]. <br>		<table><tr><td colspan='2'>[[4hvb]] 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=4HVB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HVB FirstGlance]. <br>
	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</scene><br>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</scene></td></tr>
	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [http://www.ebi.ac.uk/pdbsum/4hvb 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=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [http://www.ebi.ac.uk/pdbsum/4hvb PDBsum]</span></td></tr>
	<table>		</table>
			== Function ==
			[[http://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 25:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
	[[Category: Cheng, H.]]		[[Category: Cheng, H]]
	[[Category: Knighton, D R.]]		[[Category: Knighton, D R]]
	[[Category: Kinase]]		[[Category: Kinase]]
	[[Category: Lipid kinase]]		[[Category: Lipid kinase]]
	[[Category: Phosphoinositide kinase]]		[[Category: Phosphoinositide kinase]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 06:29, 2 July 2014

2014-07-02T06:29:25Z

← Older revision		Revision as of 06:29, 2 July 2014
Line 1:		Line 1:
	~~{{STRUCTURE_4hvb~~\| ~~PDB~~=4hvb \| ~~SCENE~~= }}		==Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064==
	===~~Catalytic unit~~ of ~~PI3Kg~~ in ~~complex~~ with PI3K/mTOR dual inhibitor PF-04979064~~===~~		<StructureSection load='4hvb' size='340' side='right' caption='[[4hvb]], [[Resolution\|resolution]] 2.35Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[4hvb]] 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=4HVB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HVB FirstGlance]. <br>
			</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=19P:1-{1-[(2S)-2-HYDROXYPROPANOYL]PIPERIDIN-4-YL}-3-METHYL-8-(6-METHYLPYRIDIN-3-YL)-1,3-DIHYDRO-2H-IMIDAZO[4,5-C][1,5]NAPHTHYRIDIN-2-ONE'>19P</scene><br>
			<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIK3CG ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
			<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4hvb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hvb OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hvb RCSB], [http://www.ebi.ac.uk/pdbsum/4hvb PDBsum]</span></td></tr>
			<table>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			PI3K, AKT, and mTOR are key kinases from PI3K signaling pathway being extensively pursued to treat a variety of cancers in oncology. To search for a structurally differentiated back-up candidate to PF-04691502, which is currently in phase I/II clinical trials for treating solid tumors, a lead optimization effort was carried out with a tricyclic imidazo[1,5]naphthyridine series. Integration of structure-based drug design and physical properties-based optimization yielded a potent and selective PI3K/mTOR dual kinase inhibitor PF-04979064. This manuscript discusses the lead optimization for the tricyclic series, which both improved the in vitro potency and addressed a number of ADMET issues including high metabolic clearance mediated by both P450 and aldehyde oxidase (AO), poor permeability, and poor solubility. An empirical scaling tool was developed to predict human clearance from in vitro human liver S9 assay data for tricyclic derivatives that were AO substrates.

	~~==Function==~~		Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04979064 through Structure-Based Drug Design.,Cheng H, Li C, Bailey S, Baxi SM, Goulet L, Guo L, Hoffman J, Jiang Y, Johnson TO, Johnson TW, Knighton DR, Li J, Liu KK, Liu Z, Marx MA, Walls M, Wells PA, Yin MJ, Zhu J, Zientek M ACS Med Chem Lett. 2012 Nov 7;4(1):91-7. doi: 10.1021/ml300309h. eCollection 2013, Jan 10. PMID:24900568<ref>PMID:24900568</ref>
	~~[[http://www.uniprot.org/uniprot~~/~~PK3CG_HUMAN PK3CG_HUMAN]] Phosphoinositide~~-3-~~kinase (PI3K) that phosphorylates PtdIns(4~~,~~5)P2 (Phosphatidylinositol 4~~,~~5-bisphosphate) to generate phosphatidylinositol 3~~,4,~~5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane~~, ~~including AKT1 and PDPK1~~, ~~activating signaling cascades involved in cell growth~~, ~~survival~~, ~~proliferation~~, ~~motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune~~, ~~inflammatory and allergic responses~~. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) ~~cell development and migration towards the sites of inflammation. Participates in T~~-~~lymphocyte migration~~. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. ~~Regulates alpha-IIb/beta-3 integrins (ITGA2B~~/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. ~~Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation~~, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.~~<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>~~PMID:~~16094730</ref>~~ <ref>PMID:~~21393242~~</ref>

	~~==About this Structure==~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	~~[[4hvb]] is~~ a ~~1 chain structure. Full crystallographic information is available from [http://oca~~.~~weizmann~~.ac.~~il/oca-bin~~/~~ocashort?id=4HVB OCA].~~		</div>

	==~~Reference~~==		==See Also==
	<references ~~group="xtra"~~/><~~references~~/>		*[[Phosphoinositide 3-Kinases\|Phosphoinositide 3-Kinases]]
			== References ==
			<references/>
			__TOC__
			</StructureSection>
			[[Category: Human]]
	[[Category: Cheng, H.]]		[[Category: Cheng, H.]]
	[[Category: Knighton, D R.]]		[[Category: Knighton, D R.]]

OCA at 13:42, 20 November 2013

2013-11-20T13:42:23Z

← Older revision		Revision as of 13:42, 20 November 2013
Line 1:		Line 1:
	~~'''Unreleased structure'''~~		{{STRUCTURE_4hvb\| PDB=4hvb \| SCENE= }}
			===Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064===

	~~The entry 4hvb~~ is ~~ON HOLD~~ ~~until Paper Publication~~		==Function==
			[[http://www.uniprot.org/uniprot/PK3CG_HUMAN PK3CG_HUMAN]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Links G-protein coupled receptor activation to PIP3 production. Involved in immune, inflammatory and allergic responses. Modulates leukocyte chemotaxis to inflammatory sites and in response to chemoattractant agents. May control leukocyte polarization and migration by regulating the spatial accumulation of PIP3 and by regulating the organization of F-actin formation and integrin-based adhesion at the leading edge. Controls motility of dendritic cells. Together with PIK3CD is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in T-lymphocyte migration. Regulates T-lymphocyte proliferation and cytokine production. Together with PIK3CD participates in T-lymphocyte development. Required for B-lymphocyte development and signaling. Together with PIK3CD participates in neutrophil respiratory burst. Together with PIK3CD is involved in neutrophil chemotaxis and extravasation. Together with PIK3CB promotes platelet aggregation and thrombosis. Regulates alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) adhesive function in platelets downstream of P2Y12 through a lipid kinase activity-independent mechanism. May have also a lipid kinase activity-dependent function in platelet aggregation. Involved in endothelial progenitor cell migration. Negative regulator of cardiac contractility. Modulates cardiac contractility by anchoring protein kinase A (PKA) and PDE3B activation, reducing cAMP levels. Regulates cardiac contractility also by promoting beta-adrenergic receptor internalization by binding to ADRBK1 and by non-muscle tropomyosin phosphorylation. Also has serine/threonine protein kinase activity: both lipid and protein kinase activities are required for beta-adrenergic receptor endocytosis. May also have a scaffolding role in modulating cardiac contractility. Contributes to cardiac hypertrophy under pathological stress. Through simultaneous binding of PDE3B to RAPGEF3 and PIK3R6 is assembled in a signaling complex in which the PI3K gamma complex is activated by RAPGEF3 and which is involved in angiogenesis.<ref>PMID:7624799</ref> <ref>PMID:12163475</ref> <ref>PMID:15294162</ref> <ref>PMID:16094730</ref> <ref>PMID:21393242</ref>

	~~Authors~~: ~~Knighton, D~~.R.~~, Cheng, H~~.		==About this Structure==
			[[4hvb]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HVB OCA].

	~~Description~~: ~~Catalytic unit of PI3Kg in~~ complex ~~with PI3K/mTOR dual inhibitor PF-04979064~~		==Reference==
			<references group="xtra"/><references/>
			[[Category: Cheng, H.]]
			[[Category: Knighton, D R.]]
			[[Category: Kinase]]
			[[Category: Lipid kinase]]
			[[Category: Phosphoinositide kinase]]
			[[Category: Transferase-transferase inhibitor complex]]

OCA at 09:07, 21 November 2012

2012-11-21T09:07:37Z

← Older revision		Revision as of 09:07, 21 November 2012
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 4hvb is ON HOLD		The entry 4hvb is ON HOLD until Paper Publication

	Authors: Knighton, D.R., Cheng, H.		Authors: Knighton, D.R., Cheng, H.

	Description: Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064		Description: Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064

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

2012-11-14T06:19:55Z

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

← Older revision	Revision as of 06:19, 14 November 2012
(No difference)

OCA: New page: '''Unreleased structure''' The entry 4hvb is ON HOLD Authors: Knighton, D.R., Cheng, H. Description: Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064

2012-11-14T06:19:54Z

New page: '''Unreleased structure''' The entry 4hvb is ON HOLD Authors: Knighton, D.R., Cheng, H. Description: Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064

New page

'''Unreleased structure'''

The entry 4hvb is ON HOLD

Authors: Knighton, D.R., Cheng, H.

Description: Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064