Abstract
We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine headgroup binds in the allylic (S1) site with the side chain in S2, but in the presence of PPi and Mg(2+), the quinuclidine's cationic center interacts with PPi and three Mg(2+), mimicking a transition state involved in diphosphate ionization. With 3, there are again two structures. In one, the geranyl side chain binds to either S1 or S2 and the adamantane headgroup binds to S1. In the second, the side chain binds to S2 while the headgroup binds to S1. These results provide structural clues for the mechanism and inhibition of the head-to-head prenyl transferases and should aid future drug design.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adamantane / analogs & derivatives
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Adamantane / chemistry
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Adamantane / pharmacology
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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / chemistry*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology*
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Ethylenediamines / chemistry
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Ethylenediamines / pharmacology
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Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*
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Farnesyl-Diphosphate Farnesyltransferase / chemistry*
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Models, Molecular
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Phenyl Ethers / chemistry
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Phenyl Ethers / pharmacology
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Quinuclidines / chemistry
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Quinuclidines / pharmacology
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Staphylococcus aureus / drug effects
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Staphylococcus aureus / enzymology*
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Thiocyanates / chemistry
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Thiocyanates / pharmacology
Substances
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4-phenoxyphenoxyethyl thiocyanate
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Bacterial Proteins
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Enzyme Inhibitors
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Ethylenediamines
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N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine
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Phenyl Ethers
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Quinuclidines
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Thiocyanates
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CrtM protein, Staphylococcus aureus
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Farnesyl-Diphosphate Farnesyltransferase
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Adamantane
Associated data
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PDB/4E9U
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PDB/4E9Z
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PDB/4EA0
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PDB/4EA1
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PDB/4EA2