Head-to-head prenyl tranferases: Anti-infective drug targets

Fu Yang Lin, Yi Liang Liu, Kai Li, Rong Cao, Wei Zhu, Jordan Axelson, Ran Pang, Eric Oldfield

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)4367-4372
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - May 10 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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