Bisphosphonates Target Multiple Sites in Both Cis and Transprenyltransferases: Structurebased drug d

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Bisphosphonates Target Multiple Sites in Both
Cis- and Trans-prenyltransferasesStructure-based
drug discovery
Publication Guo, R. T., Cao, R., Liang, P. H.,
Chang, T. H., Ko, T. P., Jeng, W. Y., Chen, C. K.
M., Hudock, M. P., Zhang, Y., Song, Y., Oldfield,
E., and Wang, A. H.-J. (2007) Bisphosphonates
target multiple sites in both cis- and
trans-prenyltransferases A crystallographic
investigation. Proc. Natl. Acad. Sci. USA, 104,
10022-10027.
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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 for the
therapy of osteoporosis. 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
anti-bacterial therapy. Our results on GGPPS (ten
structures) show that there are three
bisphosphonate binding sites, consisting of
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 since they provide the first structures
of GGPPS- and UPPS-inhibitor complexes,
potentially important new drug targets, in
addition to revealing a remarkably broad spectrum
of binding modes not seen in FPPS inhibition.
This information is critical for structure-based
drug discovery.