Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases.
Guo RT,
Cao R,
Liang PH,
Ko TP,
Chang TH,
Hudock MP,
Jeng WY,
Chen CK,
Zhang Y,
Song Y,
Kuo CJ,
Yin F,
Oldfield E,
Wang AH.
Taiwan International Graduate Program, Institute of Biological Chemistry, Core Facility for Protein Crystallography, Academia Sinica, Taipei 115, Taiwan.
Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.
PMID: 17535895 [PubMed - indexed for MEDLINE]
PMCID: PMC1877987