4olc - Revision history

OCA at 17:16, 20 September 2023

OCA — Wed, 20 Sep 2023 17:16:07 GMT

←Older revision		Revision as of 17:16, 20 September 2023
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4olc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Giardia_lamblia_ATCC_50803 Giardia lamblia ATCC 50803]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OLC FirstGlance]. <br>		<table><tr><td colspan='2'>[[4olc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Giardia_lamblia_ATCC_50803 Giardia lamblia ATCC 50803]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OLC FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</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]] 2.6Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [https://pdbe.org/4olc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [https://www.ebi.ac.uk/pdbsum/4olc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4olc 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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [https://pdbe.org/4olc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [https://www.ebi.ac.uk/pdbsum/4olc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4olc ProSAT]</span></td></tr>
	</table>		</table>

OCA at 07:31, 25 January 2023

OCA — Wed, 25 Jan 2023 07:31:19 GMT

←Older revision		Revision as of 07:31, 25 January 2023
Line 1:		Line 1:

	==Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242==		==Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242==
-	<StructureSection load='4olc' size='340' side='right' caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>	+	<StructureSection load='4olc' size='340' side='right'caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4olc]] is a 4 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Giaic Giaic~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4OLC FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4olc]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Giardia_lamblia_ATCC_50803 Giardia lamblia ATCC 50803]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OLC FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3kzf\|3kzf]], [[4jz7\|4jz7]], [[4jz8\|4jz8]], [[4jz9\|4jz9]]</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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [https://pdbe.org/4olc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [https://www.ebi.ac.uk/pdbsum/4olc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4olc ProSAT]</span></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GL50803_16453 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=184922 GIAIC])</td></tr>	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbamate_kinase Carbamate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.2.2 2.7.2.2] </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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [~~http~~://pdbe.org/4olc PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4olc PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4olc ProSAT]</span></td></tr>	+
	</table>		</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/A8BB85_GIAIC A8BB85_GIAIC]
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 23:		Line 22:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Carbamate kinase~~]]	+	[[Category: Giardia lamblia ATCC 50803]]
-	[[Category: ~~Giaic~~]]	+	[[Category: Large Structures]]
-	[[Category: Herzberg, O]]	+	[[Category: Herzberg O]]
-	[[Category: Lim, K]]	+	[[Category: Lim K]]
-	~~[[Category: Adp]]~~	+
-	~~[[Category: Carbamate]]~~	+
-	~~[[Category: Carbamoyl phosphate]]~~	+
-	~~[[Category: Mg2+]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 17:36, 11 August 2016

OCA — Thu, 11 Aug 2016 17:36:33 GMT

←Older revision		Revision as of 17:36, 11 August 2016
Line 1:		Line 1:
		+
	==Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242==		==Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242==
	<StructureSection load='4olc' size='340' side='right' caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>		<StructureSection load='4olc' size='340' side='right' caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>
Line 7:		Line 8:
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GL50803_16453 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=184922 GIAIC])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GL50803_16453 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=184922 GIAIC])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbamate_kinase Carbamate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.2.2 2.7.2.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbamate_kinase Carbamate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.2.2 2.7.2.2] </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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [http://www.ebi.ac.uk/pdbsum/4olc 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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [http://pdbe.org/4olc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [http://www.ebi.ac.uk/pdbsum/4olc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4olc ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
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 4olc" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 09:50, 5 January 2015

OCA — Mon, 05 Jan 2015 09:50:27 GMT

←Older revision		Revision as of 09:50, 5 January 2015
Line 2:		Line 2:
	<StructureSection load='4olc' size='340' side='right' caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>		<StructureSection load='4olc' size='340' side='right' caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4olc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Giaic Giaic]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. <br>	+	<table><tr><td colspan='2'>[[4olc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Giaic Giaic]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OLC FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3kzf\|3kzf]], [[4jz7\|4jz7]], [[4jz8\|4jz8]], [[4jz9\|4jz9]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3kzf\|3kzf]], [[4jz7\|4jz7]], [[4jz8\|4jz8]], [[4jz9\|4jz9]]</td></tr>
-	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GL50803_16453 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=184922 GIAIC])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GL50803_16453 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=184922 GIAIC])</td></tr>
-	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/~~Glucokinase Glucokinase~~], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbamate_kinase Carbamate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.2.2 2.7.2.2] </span></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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [http://www.ebi.ac.uk/pdbsum/4olc 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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [http://www.ebi.ac.uk/pdbsum/4olc PDBsum]</span></td></tr>
-	<table>	+	</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 15:		Line 15:
	Structural Basis for Inactivation of Giardia lamblia Carbamate Kinase by Disulfiram.,Galkin A, Kulakova L, Lim K, Chen CZ, Zheng W, Turko IV, Herzberg O J Biol Chem. 2014 Feb 20. PMID:24558036<ref>PMID:24558036</ref>		Structural Basis for Inactivation of Giardia lamblia Carbamate Kinase by Disulfiram.,Galkin A, Kulakova L, Lim K, Chen CZ, Zheng W, Turko IV, Herzberg O J Biol Chem. 2014 Feb 20. PMID:24558036<ref>PMID:24558036</ref>

-	From ~~MEDLINEÂ®~~/~~PubMedÂ®~~, 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>
	== References ==		== References ==
Line 23:		Line 23:
	[[Category: Carbamate kinase]]		[[Category: Carbamate kinase]]
	[[Category: Giaic]]		[[Category: Giaic]]
-	[[Category: Herzberg, O.]]	+	[[Category: Herzberg, O]]
-	[[Category: Lim, K.]]	+	[[Category: Lim, K]]
	[[Category: Adp]]		[[Category: Adp]]
	[[Category: Carbamate]]		[[Category: Carbamate]]

OCA at 09:41, 1 May 2014

OCA — Thu, 01 May 2014 09:41:46 GMT

←Older revision		Revision as of 09:41, 1 May 2014
Line 2:		Line 2:
	<StructureSection load='4olc' size='340' side='right' caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>		<StructureSection load='4olc' size='340' side='right' caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	[[4olc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Giaic Giaic]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. <br>	+	<table><tr><td colspan='2'>[[4olc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Giaic Giaic]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. <br>
-	<b>[[Ligand\|Ligands:]]</b> <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene><br>	+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene><br>
-	<b>[[Related_structure\|Related:]]</b> [[3kzf\|3kzf]], [[4jz7\|4jz7]], [[4jz8\|4jz8]], [[4jz9\|4jz9]]<br>	+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[3kzf\|3kzf]], [[4jz7\|4jz7]], [[4jz8\|4jz8]], [[4jz9\|4jz9]]</td></tr>
-	<b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span><br>	+	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">GL50803_16453 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=184922 GIAIC])</td></tr>
-	<b>Resources:</b> <span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [http://www.ebi.ac.uk/pdbsum/4olc PDBsum]</span><br>	+	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></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=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [http://www.ebi.ac.uk/pdbsum/4olc PDBsum]</span></td></tr>
		+	<table>
		+	<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
	Carbamate kinase from Giardia lamblia (glCK1) is an essential enzyme for the survival of the organism. The enzyme catalyzes the final step in the arginine dihydrolase pathway converting ADP and carbamoyl phosphate to ATP and carbamate. We previously reported that disulfiram, a drug used to treat chronic alcoholism, inhibits glCK and kills G. lamblia trophozoites in vitro at submicromolar IC50 values. Here we examine the structural basis for glCK inhibition of disulfiram and its analog, thiram, their activities against both metronidazole-susceptible and metronidazole-resistant G. lamblia isolates, and their efficacy in a mouse model of Giardiasis. The crystal structure of glCK soaked with disulfiram revealed that the compound thiocarbamoylated Cys242, a residue located at the edge of the active site. The modified Cys242 prevents a conformational transition of a loop adjacent to the ADP/ATP binding site, which is required for the stacking of Tyr245 side chain against the adenine moiety, an interaction seen in the structure of glCK in complex with AMP-PNP. Mass spectrometry coupled with trypsin digestion confirmed the selective covalent thiocarbamoylation of Cys242 in solution. The G. lamblia viability studies in the metronidazole-resistant strain and the glCK irreversible inactivation mechanism show that the thiuram compounds can circumvent the resistance mechanism that renders metronidazole ineffectiveness in drug resistance cases of giardiasis. Together, the studies suggest that glCK is an attractive drug target for development of novel antigiardial therapies, and that disulfiram, a FDA approved drug, is a promising candidate for drug repurposing.		Carbamate kinase from Giardia lamblia (glCK1) is an essential enzyme for the survival of the organism. The enzyme catalyzes the final step in the arginine dihydrolase pathway converting ADP and carbamoyl phosphate to ATP and carbamate. We previously reported that disulfiram, a drug used to treat chronic alcoholism, inhibits glCK and kills G. lamblia trophozoites in vitro at submicromolar IC50 values. Here we examine the structural basis for glCK inhibition of disulfiram and its analog, thiram, their activities against both metronidazole-susceptible and metronidazole-resistant G. lamblia isolates, and their efficacy in a mouse model of Giardiasis. The crystal structure of glCK soaked with disulfiram revealed that the compound thiocarbamoylated Cys242, a residue located at the edge of the active site. The modified Cys242 prevents a conformational transition of a loop adjacent to the ADP/ATP binding site, which is required for the stacking of Tyr245 side chain against the adenine moiety, an interaction seen in the structure of glCK in complex with AMP-PNP. Mass spectrometry coupled with trypsin digestion confirmed the selective covalent thiocarbamoylation of Cys242 in solution. The G. lamblia viability studies in the metronidazole-resistant strain and the glCK irreversible inactivation mechanism show that the thiuram compounds can circumvent the resistance mechanism that renders metronidazole ineffectiveness in drug resistance cases of giardiasis. Together, the studies suggest that glCK is an attractive drug target for development of novel antigiardial therapies, and that disulfiram, a FDA approved drug, is a promising candidate for drug repurposing.
Line 13:		Line 16:

	From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>		From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 10:15, 30 April 2014

OCA — Wed, 30 Apr 2014 10:15:40 GMT

←Older revision		Revision as of 10:15, 30 April 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	[[4olc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Giaic Giaic]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. <br>		[[4olc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Giaic Giaic]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. <br>
-	<b>Related:</b> [[3kzf\|3kzf]], [[4jz7\|4jz7]], [[4jz8\|4jz8]], [[4jz9\|4jz9]]<br>	+	<b>[[Ligand\|Ligands:]]</b> <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DCD:DIETHYLCARBAMODITHIOIC+ACID'>DCD</scene><br>
		+	<b>[[Related_structure\|Related:]]</b> [[3kzf\|3kzf]], [[4jz7\|4jz7]], [[4jz8\|4jz8]], [[4jz9\|4jz9]]<br>
	<b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span><br>		<b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span><br>
		+	<b>Resources:</b> <span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4olc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4olc OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4olc RCSB], [http://www.ebi.ac.uk/pdbsum/4olc PDBsum]</span><br>
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
	Carbamate kinase from Giardia lamblia (glCK1) is an essential enzyme for the survival of the organism. The enzyme catalyzes the final step in the arginine dihydrolase pathway converting ADP and carbamoyl phosphate to ATP and carbamate. We previously reported that disulfiram, a drug used to treat chronic alcoholism, inhibits glCK and kills G. lamblia trophozoites in vitro at submicromolar IC50 values. Here we examine the structural basis for glCK inhibition of disulfiram and its analog, thiram, their activities against both metronidazole-susceptible and metronidazole-resistant G. lamblia isolates, and their efficacy in a mouse model of Giardiasis. The crystal structure of glCK soaked with disulfiram revealed that the compound thiocarbamoylated Cys242, a residue located at the edge of the active site. The modified Cys242 prevents a conformational transition of a loop adjacent to the ADP/ATP binding site, which is required for the stacking of Tyr245 side chain against the adenine moiety, an interaction seen in the structure of glCK in complex with AMP-PNP. Mass spectrometry coupled with trypsin digestion confirmed the selective covalent thiocarbamoylation of Cys242 in solution. The G. lamblia viability studies in the metronidazole-resistant strain and the glCK irreversible inactivation mechanism show that the thiuram compounds can circumvent the resistance mechanism that renders metronidazole ineffectiveness in drug resistance cases of giardiasis. Together, the studies suggest that glCK is an attractive drug target for development of novel antigiardial therapies, and that disulfiram, a FDA approved drug, is a promising candidate for drug repurposing.		Carbamate kinase from Giardia lamblia (glCK1) is an essential enzyme for the survival of the organism. The enzyme catalyzes the final step in the arginine dihydrolase pathway converting ADP and carbamoyl phosphate to ATP and carbamate. We previously reported that disulfiram, a drug used to treat chronic alcoholism, inhibits glCK and kills G. lamblia trophozoites in vitro at submicromolar IC50 values. Here we examine the structural basis for glCK inhibition of disulfiram and its analog, thiram, their activities against both metronidazole-susceptible and metronidazole-resistant G. lamblia isolates, and their efficacy in a mouse model of Giardiasis. The crystal structure of glCK soaked with disulfiram revealed that the compound thiocarbamoylated Cys242, a residue located at the edge of the active site. The modified Cys242 prevents a conformational transition of a loop adjacent to the ADP/ATP binding site, which is required for the stacking of Tyr245 side chain against the adenine moiety, an interaction seen in the structure of glCK in complex with AMP-PNP. Mass spectrometry coupled with trypsin digestion confirmed the selective covalent thiocarbamoylation of Cys242 in solution. The G. lamblia viability studies in the metronidazole-resistant strain and the glCK irreversible inactivation mechanism show that the thiuram compounds can circumvent the resistance mechanism that renders metronidazole ineffectiveness in drug resistance cases of giardiasis. Together, the studies suggest that glCK is an attractive drug target for development of novel antigiardial therapies, and that disulfiram, a FDA approved drug, is a promising candidate for drug repurposing.

OCA at 05:28, 30 April 2014

OCA — Wed, 30 Apr 2014 05:28:02 GMT

←Older revision		Revision as of 05:28, 30 April 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4olc\| PDB=4olc \| SCENE= }}~~	+	==Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242==
-	===Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242===	+	<StructureSection load='4olc' size='340' side='right' caption='[[4olc]], [[Resolution\|resolution]] 2.60Å' scene=''>
-	~~{{ABSTRACT_PUBMED_24558036}}~~	+	== Structural highlights ==
		+	[[4olc]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Giaic Giaic]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA]. <br>
		+	<b>Related:</b> [[3kzf\|3kzf]], [[4jz7\|4jz7]], [[4jz8\|4jz8]], [[4jz9\|4jz9]]<br>
		+	<b>Activity:</b> <span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span><br>
		+	== Publication Abstract from PubMed ==
		+	Carbamate kinase from Giardia lamblia (glCK1) is an essential enzyme for the survival of the organism. The enzyme catalyzes the final step in the arginine dihydrolase pathway converting ADP and carbamoyl phosphate to ATP and carbamate. We previously reported that disulfiram, a drug used to treat chronic alcoholism, inhibits glCK and kills G. lamblia trophozoites in vitro at submicromolar IC50 values. Here we examine the structural basis for glCK inhibition of disulfiram and its analog, thiram, their activities against both metronidazole-susceptible and metronidazole-resistant G. lamblia isolates, and their efficacy in a mouse model of Giardiasis. The crystal structure of glCK soaked with disulfiram revealed that the compound thiocarbamoylated Cys242, a residue located at the edge of the active site. The modified Cys242 prevents a conformational transition of a loop adjacent to the ADP/ATP binding site, which is required for the stacking of Tyr245 side chain against the adenine moiety, an interaction seen in the structure of glCK in complex with AMP-PNP. Mass spectrometry coupled with trypsin digestion confirmed the selective covalent thiocarbamoylation of Cys242 in solution. The G. lamblia viability studies in the metronidazole-resistant strain and the glCK irreversible inactivation mechanism show that the thiuram compounds can circumvent the resistance mechanism that renders metronidazole ineffectiveness in drug resistance cases of giardiasis. Together, the studies suggest that glCK is an attractive drug target for development of novel antigiardial therapies, and that disulfiram, a FDA approved drug, is a promising candidate for drug repurposing.

-	~~==About this Structure==~~	+	Structural Basis for Inactivation of Giardia lamblia Carbamate Kinase by Disulfiram.,Galkin A, Kulakova L, Lim K, Chen CZ, Zheng W, Turko IV, Herzberg O J Biol Chem. 2014 Feb 20. PMID:24558036<ref>PMID:24558036</ref>
-	~~[[4olc]] is a 4 chain structure~~. ~~Full crystallographic information is available from [http://oca~~.~~weizmann~~.~~ac.il~~/~~oca-bin/ocashort?id=4OLC OCA].~~	+

-	==~~Reference~~==	+	From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
-	~~<ref group="xtra">PMID:024558036</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Carbamate kinase]]		[[Category: Carbamate kinase]]
		+	[[Category: Giaic]]
	[[Category: Herzberg, O.]]		[[Category: Herzberg, O.]]
	[[Category: Lim, K.]]		[[Category: Lim, K.]]

OCA at 08:01, 26 March 2014

OCA — Wed, 26 Mar 2014 08:01:14 GMT

←Older revision		Revision as of 08:01, 26 March 2014
Line 1:		Line 1:
	{{STRUCTURE_4olc\| PDB=4olc \| SCENE= }}		{{STRUCTURE_4olc\| PDB=4olc \| SCENE= }}
	===Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242===		===Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242===
-	{{~~ABSTRACT_PUBMED_20383005~~}}	+	{{ABSTRACT_PUBMED_24558036}}

	==About this Structure==		==About this Structure==
Line 7:		Line 7:

	==Reference==		==Reference==
-	<ref group="xtra">PMID:~~020383005~~</ref><references group="xtra"/><references/>	+	<ref group="xtra">PMID:024558036</ref><references group="xtra"/><references/>
	[[Category: Carbamate kinase]]		[[Category: Carbamate kinase]]
	[[Category: Herzberg, O.]]		[[Category: Herzberg, O.]]

OCA at 18:13, 3 March 2014

OCA — Mon, 03 Mar 2014 18:13:10 GMT

←Older revision		Revision as of 18:13, 3 March 2014
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	{{STRUCTURE_4olc\| PDB=4olc \| SCENE= }}
		+	===Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242===
		+	{{ABSTRACT_PUBMED_20383005}}

-	~~The entry~~ 4olc is ~~ON HOLD~~	+	==About this Structure==
		+	[[4olc]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OLC OCA].

-	~~Authors~~: ~~Lim, K.,~~ Herzberg, O.	+	==Reference==
-		+	<ref group="xtra">PMID:020383005</ref><references group="xtra"/><references/>
-	~~Description~~: Carbamate ~~kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242~~	+	[[Category: Carbamate kinase]]
		+	[[Category: Herzberg, O.]]
		+	[[Category: Lim, K.]]
		+	[[Category: Adp]]
		+	[[Category: Carbamate]]
		+	[[Category: Carbamoyl phosphate]]
		+	[[Category: Mg2+]]
		+	[[Category: Transferase]]

OCA at 10:31, 5 February 2014

OCA — Wed, 05 Feb 2014 10:31:30 GMT

←Older revision		Revision as of 10:31, 5 February 2014
Line 5:		Line 5:
	Authors: Lim, K., Herzberg, O.		Authors: Lim, K., Herzberg, O.

-	Description: ~~carbamate~~ kinase from Giardia lamblia ~~thiocabamoylated~~ by disulfiram on Cys242	+	Description: Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242