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Crystal structure of the human squalene synthase in complex with zaragozic acid ACrystal structure of the human squalene synthase in complex with zaragozic acid A
Structural highlights
FunctionPublication Abstract from PubMedZaragozic 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. Binding modes of zaragozic acid A to human squalene synthase and staphylococcal dehydrosqualene synthase.,Liu CI, Jeng WY, Chang WJ, Ko TP, Wang AH J Biol Chem. 2012 May 25;287(22):18750-7. Epub 2012 Apr 3. PMID:22474324[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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