title: Head-to-head prenyl tranferases: anti-infective drug targets.
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.
authors.affiliation: Center for Biophysics and Computational Biology,University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Fu-Yang
authors.initials: FY
authors.lastname: Lin
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Liu
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Cao
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Jordan
authors.initials: J
authors.lastname: Axelson
authors.forename: Ran
authors.initials: R
authors.lastname: Pang
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005029:Ethylenediamines / Q000737:chemistry / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D008958:Models, Molecular; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology; D011812:Quinuclidines / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013861:Thiocyanates / Q000737:chemistry / Q000494:pharmacology
chemical_list: C111921:4-phenoxyphenoxyethyl thiocyanate; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D005029:Ethylenediamines; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D010647:Phenyl Ethers; D011812:Quinuclidines; D013861:Thiocyanates; C091056:CrtM protein, Staphylococcus aureus; D013186:Farnesyl-Diphosphate Farnesyltransferase; D000218:Adamantane