3VJC

Crystal structure of the human squalene synthase in complex with zaragozic acid A

3VJC の概要

• エントリーDOI: 10.2210/pdb3vjc/pdb
• 関連するPDBエントリー: 3VJ8 3VJ9 3VJA 3VJB 3VJD 3VJE
• 分子名称: Squalene synthase, Zaragozic acid A, PHOSPHATE ION, ... (5 entities in total)
• 機能のキーワード: farnesyl-diphosphate farnesyltransferase, head-to-head synthases, cholesterol biosynthesis, oxidoreductase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Multi-pass membrane protein: P37268
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 241456.64

構造登録者

Liu, C.I.,Jeng, W.Y.,Chang, W.J.,Ko, T.P.,Wang, A.H.J. (登録日: 2011-10-14, 公開日: 2012-04-11, 最終更新日: 2023-11-08)

主引用文献

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

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: 22474324
DOI: 10.1074/jbc.M112.351254

実験手法

X-RAY DIFFRACTION (1.89 Å)