3VJC
Crystal structure of the human squalene synthase in complex with zaragozic acid A
Summary for 3VJC
| Entry DOI | 10.2210/pdb3vjc/pdb |
| Related | 3VJ8 3VJ9 3VJA 3VJB 3VJD 3VJE |
| Descriptor | Squalene synthase, Zaragozic acid A, PHOSPHATE ION, ... (5 entities in total) |
| Functional Keywords | farnesyl-diphosphate farnesyltransferase, head-to-head synthases, cholesterol biosynthesis, oxidoreductase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Endoplasmic reticulum membrane; Multi-pass membrane protein: P37268 |
| Total number of polymer chains | 6 |
| Total formula weight | 241456.64 |
| Authors | Liu, C.I.,Jeng, W.Y.,Chang, W.J.,Ko, T.P.,Wang, A.H.J. (deposition date: 2011-10-14, release date: 2012-04-11, Last modification date: 2023-11-08) |
| Primary citation | Liu, C.I.,Jeng, W.Y.,Chang, W.J.,Ko, T.P.,Wang, A.H.J. Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase J.Biol.Chem., 287:18750-18757, 2012 Cited by PubMed Abstract: Zaragozic acids (ZAs) belong to a family of fungal metabolites with nanomolar inhibitory activity toward squalene synthase (SQS). The enzyme catalyzes the committed step of sterol synthesis and has attracted attention as a potential target for antilipogenic and antiinfective therapies. Here, we have determined the structure of ZA-A complexed with human SQS. ZA-A binding induces a local conformational change in the substrate binding site, and its C-6 acyl group also extends over to the cofactor binding cavity. In addition, ZA-A effectively inhibits a homologous bacterial enzyme, dehydrosqualene synthase (CrtM), which synthesizes the precursor of staphyloxanthin in Staphylococcus aureus to cope with oxidative stress. Size reduction at Tyr(248) in CrtM further increases the ZA-A binding affinity, and it reveals a similar overall inhibitor binding mode to that of human SQS/ZA-A except for the C-6 acyl group. These structures pave the way for further improving selectivity and development of a new generation of anticholesterolemic and antimicrobial inhibitors. PubMed: 22474324DOI: 10.1074/jbc.M112.351254 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.89 Å) |
Structure validation
Download full validation report
