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Title
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Crystal structure of a squalene cyclase in complex with the potential anticholesteremic drug Ro48-8071.
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Authors
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A.Lenhart,
W.A.Weihofen,
A.E.Pleschke,
G.E.Schulz.
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Ref.
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Chem Biol, 2002,
9,
639-645.
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PubMed id
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Abstract
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Squalene-hopene cyclase (SHC) catalyzes the conversion of squalene into
pentacyclic compounds. It is the prokaryotic counterpart of the eukaryotic
oxidosqualene cyclase (OSC) that catalyzes the steroid scaffold formation.
Because of clear sequence homology, SHC can serve as a model for OSC, which is
an attractive target for anticholesteremic drugs. We have established the
crystal structure of SHC complexed with Ro48-8071, a potent inhibitor of OSC and
therefore of cholesterol biosynthesis. Ro48-8071 is bound in the active-center
cavity of SHC and extends into the channel that connects the cavity with the
membrane. The binding site of Ro48-8071 is largely identical with the expected
site of squalene; it differs from a previous model based on photoaffinity
labeling. The knowledge of the inhibitor binding mode in SHC is likely to help
develop more potent inhibitors for OSC.
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