Abstract
The binding structures of 11 human oxidosqualene cyclase inhibitors designed as cholesterol-lowering agents were determined for the squalene-hopene cyclase from Alicyclobacillus acidocaldarius, which is the only structurally known homologue of the human enzyme. The complexes were produced by cocrystallization, and the structures were elucidated by X-ray diffraction analyses. All inhibitors were bound in the large active center cavity. The detailed binding structures are presented and discussed in the light of the IC50 values of these 11 as well as 17 other inhibitors. They provide a consistent picture for the inhibition of the bacterial enzyme and can be used to adjust and improve homology models of the human enzyme. The detailed active center structures of the two enzymes are too different to show an IC50 correlation.
MeSH terms
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Amines / chemistry
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Anticholesteremic Agents / chemistry*
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Anticholesteremic Agents / pharmacology
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Bacillaceae / chemistry
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Benzene Derivatives / chemistry
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Benzophenones / chemistry
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Benzophenones / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Cyclopropanes / chemistry
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Humans
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In Vitro Techniques
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Intramolecular Transferases / antagonists & inhibitors*
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Intramolecular Transferases / chemistry
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Models, Molecular
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Protein Binding
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Structure-Activity Relationship
Substances
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Amines
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Anticholesteremic Agents
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Benzene Derivatives
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Benzophenones
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Cyclopropanes
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Enzyme Inhibitors
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Intramolecular Transferases
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squalene-hopene cyclase
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lanosterol synthase
Associated data
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PDB/1GSZ
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PDB/1H35
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PDB/1H36
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PDB/1H37
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PDB/1H39
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PDB/1H3A
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PDB/1H3B
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PDB/1H3C
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PDB/1O6H
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PDB/1O6Q
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PDB/1O6R
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PDB/1O79