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PDBsum entry 3vjc
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Transferase/transferase inhibitor
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PDB id
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3vjc
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References listed in PDB file
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Key reference
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Title
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Binding modes of zaragozic acid a to human squalene synthase and staphylococcal dehydrosqualene synthase.
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Authors
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C.I.Liu,
W.Y.Jeng,
W.J.Chang,
T.P.Ko,
A.H.Wang.
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Ref.
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J Biol Chem, 2012,
287,
18750-18757.
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PubMed id
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Abstract
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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.
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