3WCJ

The complex structure of HsSQS wtih ligand,E5700

Summary for 3WCJ

• Entry DOI: 10.2210/pdb3wcj/pdb
• Related: 3WC9 3WCA 3WCB 3WCC 3WCD 3WCE 3WCF 3WCG 3WCH 3WCI 3WCL 3WCM
• Descriptor: Squalene synthase, (3R)-3-({2-benzyl-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridin-3-yl}ethynyl)-1-azabicyclo[2.2.2]octan-3-ol (3 entities in total)
• Functional Keywords: isoprenoids, drug discovery, human squalene synthase, transferase, e5700
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Multi-pass membrane protein: P37268
• Total number of polymer chains: 6
• Total formula weight: 250335.19

Authors

Shang, N.,Li, Q.,Ko, T.P.,Chan, H.C.,Huang, C.H.,Ren, F.,Zheng, Y.,Zhu, Z.,Chen, C.C.,Guo, R.T. (deposition date: 2013-05-27, release date: 2014-06-18, Last modification date: 2023-11-08)

Primary citation

Shang, N.,Li, Q.,Ko, T.P.,Chan, H.C.,Li, J.,Zheng, Y.,Huang, C.H.,Ren, F.,Chen, C.C.,Zhu, Z.,Galizzi, M.,Li, Z.H.,Rodrigues-Poveda, C.A.,Gonzalez-Pacanowska, D.,Veiga-Santos, P.,de Carvalho, T.M.,de Souza, W.,Urbina, J.A.,Wang, A.H.,Docampo, R.,Li, K.,Liu, Y.L.,Oldfield, E.,Guo, R.T.
Squalene synthase as a target for Chagas disease therapeutics.
Plos Pathog., 10:e1004114-e1004114, 2014

PubMed Abstract: 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.

PubMed: 24789335
DOI: 10.1371/journal.ppat.1004114

Experimental method

X-RAY DIFFRACTION (2.2 Å)