View source for 4olc


==Carbamate kinase from Giardia lamblia thiocarbamoylated by disulfiram on Cys242==
<StructureSection load='4olc' size='340' side='right'caption='[[4olc]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
== 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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6&#8491;</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>
</table>
== Function ==
[https://www.uniprot.org/uniprot/A8BB85_GIAIC A8BB85_GIAIC] 
<div style="background-color:#fffaf0;">
== 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.

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 MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4olc" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Giardia lamblia ATCC 50803]]
[[Category: Large Structures]]
[[Category: Herzberg O]]
[[Category: Lim K]]