View source for 3wce


==The complex structure of TcSQS with ligand, ER119884==
<StructureSection load='3wce' size='340' side='right' caption='[[3wce]], [[Resolution|resolution]] 2.75&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3wce]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WCE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3WCE FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ER4:(3R)-3-{[2-BENZYL-6-(3-METHOXYPROPOXY)PYRIDIN-3-YL]ETHYNYL}-1-AZABICYCLO[2.2.2]OCTAN-3-OL'>ER4</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3wca|3wca]], [[3wc9|3wc9]], [[3wcb|3wcb]], [[3wcc|3wcc]], [[3wcd|3wcd]], [[3wcf|3wcf]], [[3wcg|3wcg]], [[3wch|3wch]], [[3wci|3wci]], [[3wcj|3wcj]], [[3wcl|3wcl]], [[3wcm|3wcm]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Squalene_synthase Squalene synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.21 2.5.1.21] </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=3wce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wce OCA], [http://pdbe.org/3wce PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3wce RCSB], [http://www.ebi.ac.uk/pdbsum/3wce PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3wce ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.

Squalene synthase as a target for Chagas disease therapeutics.,Shang N, Li Q, Ko TP, Chan HC, Li J, Zheng Y, Huang CH, Ren F, Chen CC, Zhu Z, Galizzi M, Li ZH, Rodrigues-Poveda CA, Gonzalez-Pacanowska D, Veiga-Santos P, de Carvalho TM, de Souza W, Urbina JA, Wang AH, Docampo R, Li K, Liu YL, Oldfield E, Guo RT PLoS Pathog. 2014 May 1;10(5):e1004114. doi: 10.1371/journal.ppat.1004114., eCollection 2014 May. PMID:24789335<ref>PMID:24789335</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3wce" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Squalene synthase]]
[[Category: Chan, H C]]
[[Category: Chen, C C]]
[[Category: Guo, R T]]
[[Category: Huang, C H]]
[[Category: Ko, T P]]
[[Category: Li, Q]]
[[Category: Ren, F]]
[[Category: Shang, N]]
[[Category: Zheng, Y]]
[[Category: Zhu, Z]]
[[Category: Drug discovery]]
[[Category: Er-119884]]
[[Category: Isoprenoid]]
[[Category: Transferase]]
[[Category: Trypanosoma cruzi squalene synthase]]