6bfa - Revision history

OCA at 14:21, 13 March 2024

2024-03-13T14:21:58Z

←Older revision		Revision as of 14:21, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='6bfa' size='340' side='right'caption='[[6bfa]], [[Resolution\|resolution]] 2.80Å' scene=''>		<StructureSection load='6bfa' size='340' side='right'caption='[[6bfa]], [[Resolution\|resolution]] 2.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6bfa]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Toxgo Toxgo~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BFA OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6BFA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6bfa]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Toxoplasma_gondii Toxoplasma gondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BFA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BFA FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name='pdbligand=UW5:1-{4-amino-3-[6-(cyclopropyloxy)naphthalen-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-methylpropan-2-ol'>UW5</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]] 2.8Å</td></tr>
-	~~<tr~~ id~~='related'><td class~~="~~sblockLbl~~">~~<b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ona\|4ona]]~~, [[~~4tzr~~\|~~4tzr]], [[4wg5\|4wg5~~]]</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=UW5:1-{4-amino-3-[6-(cyclopropyloxy)naphthalen-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-methylpropan-2-ol'>UW5</scene></td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>CDPK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id~~=5811 TOXGO])</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=6bfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfa OCA], [https://pdbe.org/6bfa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bfa RCSB], [https://www.ebi.ac.uk/pdbsum/6bfa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfa ProSAT]</span></td></tr>
-	~~<tr id='activity'><td class~~="~~sblockLbl~~"><~~b>Activity:</b></td><td class~~=~~"sblockDat"><span class~~=~~'plainlinks'>[http~~:~~//en.wikipedia.org/wiki/Calcium/calmodulin~~-~~dependent_protein_kinase Calcium/calmodulin~~-~~dependent protein kinase~~]~~, with EC number~~ [~~http://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=~~2~~.7.11.17~~ 2~~.7.11.17]~~ </~~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=6bfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfa OCA], [~~http~~://pdbe.org/6bfa PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6bfa RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6bfa PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfa ProSAT]</span></td></tr>	+
	</table>		</table>
-	~~<div style~~=~~"background-color:#fffaf0;">~~	+	== Function ==
-	=~~= Publication Abstract from PubMed~~ ==	+	[https://www.uniprot.org/uniprot/A0A0F7UUA6_TOXGV A0A0F7UUA6_TOXGV]
-	New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. ~~These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy~~.	+

-	Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.,Vidadala RS, Rivas KL, Ojo KK, Hulverson MA, Zambriski JA, Bruzual I, Schultz TL, Huang W, Zhang Z, Scheele S, DeRocher AE, Choi R, Barrett LK, Siddaramaiah LK, Hol WG, Fan E, Merritt EA, Parsons M, Freiberg G, Marsh K, Kempf DJ, Carruthers VB, Isoherranen N, Doggett JS, Van Voorhis WC, Maly DJ J Med Chem. 2016 Jul 14;59(13):6531-46. doi: 10.1021/acs.jmedchem.6b00760. Epub, 2016 Jul 1. PMID:27309760<ref>PMID:27309760</ref>	+	==See Also==
-		+	*[[Calcium-dependent protein kinase\|Calcium-dependent protein kinase]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6bfa" style~~=~~"background-color:#fffaf0;"></div>~~	+
-	~~== References~~ ==	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: Calcium/calmodulin-dependent protein kinase]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Toxgo~~]]	+	[[Category: Toxoplasma gondii]]
-	[[Category: Merritt~~, E A]]~~	+	[[Category: Merritt EA]]
-	~~[[Category: Bumped kinase inhibitor]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 17:44, 11 December 2019

2019-12-11T17:44:50Z

←Older revision		Revision as of 17:44, 11 December 2019
Line 1:		Line 1:

	==Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1553==		==Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1553==
-	<StructureSection load='6bfa' size='340' side='right' caption='[[6bfa]], [[Resolution\|resolution]] 2.80Å' scene=''>	+	<StructureSection load='6bfa' size='340' side='right'caption='[[6bfa]], [[Resolution\|resolution]] 2.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6bfa]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BFA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6bfa]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Toxgo Toxgo]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BFA FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=UW5:1-{4-amino-3-[6-(cyclopropyloxy)naphthalen-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-methylpropan-2-ol'>UW5</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=UW5:1-{4-amino-3-[6-(cyclopropyloxy)naphthalen-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-methylpropan-2-ol'>UW5</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ona\|4ona]], [[4tzr\|4tzr]], [[4wg5\|4wg5]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ona\|4ona]], [[4tzr\|4tzr]], [[4wg5\|4wg5]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CDPK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=5811 TOXGO])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Calcium/calmodulin-dependent_protein_kinase Calcium/calmodulin-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.17 2.7.11.17] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Calcium/calmodulin-dependent_protein_kinase Calcium/calmodulin-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.17 2.7.11.17] </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=6bfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfa OCA], [http://pdbe.org/6bfa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bfa RCSB], [http://www.ebi.ac.uk/pdbsum/6bfa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfa 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=6bfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfa OCA], [http://pdbe.org/6bfa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bfa RCSB], [http://www.ebi.ac.uk/pdbsum/6bfa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfa ProSAT]</span></td></tr>
Line 23:		Line 24:
	</StructureSection>		</StructureSection>
	[[Category: Calcium/calmodulin-dependent protein kinase]]		[[Category: Calcium/calmodulin-dependent protein kinase]]
		+	[[Category: Large Structures]]
		+	[[Category: Toxgo]]
	[[Category: Merritt, E A]]		[[Category: Merritt, E A]]
	[[Category: Bumped kinase inhibitor]]		[[Category: Bumped kinase inhibitor]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 07:25, 6 December 2017

2017-12-06T07:25:21Z

←Older revision		Revision as of 07:25, 6 December 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6bfa is ~~ON HOLD~~	+	==Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1553==
		+	<StructureSection load='6bfa' size='340' side='right' caption='[[6bfa]], [[Resolution\|resolution]] 2.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6bfa]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6BFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BFA FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=UW5:1-{4-amino-3-[6-(cyclopropyloxy)naphthalen-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-2-methylpropan-2-ol'>UW5</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4ona\|4ona]], [[4tzr\|4tzr]], [[4wg5\|4wg5]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Calcium/calmodulin-dependent_protein_kinase Calcium/calmodulin-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.17 2.7.11.17] </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=6bfa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfa OCA], [http://pdbe.org/6bfa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bfa RCSB], [http://www.ebi.ac.uk/pdbsum/6bfa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfa ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.

-	~~Authors: Merritt~~, E.A.	+	Development of an Orally Available and Central Nervous System (CNS) Penetrant Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitor with Minimal Human Ether-a-go-go-Related Gene (hERG) Activity for the Treatment of Toxoplasmosis.,Vidadala RS, Rivas KL, Ojo KK, Hulverson MA, Zambriski JA, Bruzual I, Schultz TL, Huang W, Zhang Z, Scheele S, DeRocher AE, Choi R, Barrett LK, Siddaramaiah LK, Hol WG, Fan E, Merritt EA, Parsons M, Freiberg G, Marsh K, Kempf DJ, Carruthers VB, Isoherranen N, Doggett JS, Van Voorhis WC, Maly DJ J Med Chem. 2016 Jul 14;59(13):6531-46. doi: 10.1021/acs.jmedchem.6b00760. Epub, 2016 Jul 1. PMID:27309760<ref>PMID:27309760</ref>

-	~~Description: Calcium~~-~~Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1553~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: Merritt, E.A]]	+	<div class="pdbe-citations 6bfa" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Calcium/calmodulin-dependent protein kinase]]
		+	[[Category: Merritt, E A]]
		+	[[Category: Bumped kinase inhibitor]]
		+	[[Category: Transferase-transferase inhibitor complex]]

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

2017-11-01T05:01:41Z

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

←Older revision

Revision as of 05:01, 1 November 2017

OCA: New page: '''Unreleased structure''' The entry 6bfa is ON HOLD Authors: Merritt, E.A. Description: Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor U...

2017-11-01T05:01:40Z

New page: '''Unreleased structure''' The entry 6bfa is ON HOLD Authors: Merritt, E.A. Description: Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor U...

New page

'''Unreleased structure'''

The entry 6bfa is ON HOLD

Authors: Merritt, E.A.

Description: Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii (TgCDPK1) in complex with inhibitor UW1553
[[Category: Unreleased Structures]]
[[Category: Merritt, E.A]]