3WEH

Crystal structure of the human squalene synthase in complex with presqualene pyrophosphate

Summary for 3WEH

• Entry DOI: 10.2210/pdb3weh/pdb
• Related: 3VJ8 3VJ9 3VJA 3VJB 3VJC 3VJD 3WEF 3WEG 3WEI 3WEJ 3WEK
• Descriptor: Squalene synthase, MAGNESIUM ION, {(1R,2R,3R)-2-[(3E)-4,8-dimethylnona-3,7-dien-1-yl]-2-methyl-3-[(1E,5E)-2,6,10-trimethylundeca-1,5,9-trien-1-yl]cyclopropyl}methyl trihydrogen diphosphate, ... (4 entities in total)
• Functional Keywords: farnesyl-diphosphate farnesyltransferase, head-to-head synthases, cholesterol biosynthesis, oxidoreductase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 40084.26

Authors

Liu, C.I.,Jeng, W.Y.,Wang, A.H.J. (deposition date: 2013-07-07, release date: 2014-02-12, Last modification date: 2023-11-08)

Primary citation

Liu, C.I.,Jeng, W.Y.,Chang, W.J.,Shih, M.F.,Ko, T.P.,Wang, A.H.J.
Structural insights into the catalytic mechanism of human squalene synthase.
Acta Crystallogr.,Sect.D, 70:231-241, 2014

PubMed Abstract: Squalene synthase (SQS) is a divalent metal-ion-dependent enzyme that catalyzes the two-step reductive `head-to-head' condensation of two molecules of farnesyl pyrophosphate to form squalene using presqualene diphosphate (PSPP) as an intermediate. In this paper, the structures of human SQS and its mutants in complex with several substrate analogues and intermediates coordinated with Mg2+ or Mn2+ are presented, which stepwise delineate the biosynthetic pathway. Extensive study of the SQS active site has identified several critical residues that are involved in binding reduced nicotinamide dinucleotide phosphate (NADPH). Based on mutagenesis data and a locally closed (JK loop-in) structure observed in the hSQS-(F288L)-PSPP complex, an NADPH-binding model is proposed for SQS. The results identified four major steps (substrate binding, condensation, intermediate formation and translocation) of the ordered sequential mechanisms involved in the `1'-1' isoprenoid biosynthetic pathway. These new findings clarify previous hypotheses based on site-directed mutagenesis and biochemical analysis.

PubMed: 24531458
DOI: 10.1107/S1399004713026230

Experimental method

X-RAY DIFFRACTION (1.87 Å)