Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases

Rong Cao, Cammy K.M. Chen, Rey Ting Guo, Andrew H.J. Wang, Eric Oldfield

Research output: Contribution to journalArticlepeer-review

Abstract

We report the X-ray crystallographic structures of the bisphosphonate N-[methyl(4-phenylbutyl)]-3-aminopropyl-1-hydroxy-1,1-bisphosphonate (BPH-210), a potent analog of pamidronate (Aredia), bound to farnesyl diphosphate synthase (FPPS) from Trypanosoma brucei as well as to geranylgeranyl diphosphate synthase from Saccharomyces cerevisiae. BPH-210 binds to FPPS, together with 3 Mg 2+, with its long, hydrophobic phenylbutyl side-chain being located in the same binding pocket that is occupied by allylic diphosphates and other bisphosphonates. Binding is overwhelmingly entropy driven, as determined by isothermal titration calorimetry. The structure is of interest since it explains the lack of potency of longer chain analogs against FPPS, since these would be expected to have a steric clash with an aromatic ring at the distal end of the binding site. Unlike shorter chain FPPS inhibitors, such as pamidronate, BPH-210 is also found to be a potent inhibitor of human geranylgeranyl diphosphate synthase. In this case, the bisphosphonate binds only to the GGPP product inhibitory site, with only 1 (chain A) or 0 (chain B) Mg2+, and ΔS is much smaller and ΔH is ∼6 k cal more negative than in the case of FPPS binding. Overall, these results are of general interest since they show that some bisphosphonates can bind to more than one trans-prenyl synthase enzyme which, in some cases, can be expected to enhance their overall activity in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)431-439
Number of pages9
JournalProteins: Structure, Function and Genetics
Volume73
Issue number2
DOIs
StatePublished - Nov 1 2008

Keywords

  • Bisphosphonate
  • Farnesyl diphosphate synthase
  • Geranylgeranyl diphosphate synthase
  • Isoprenoid biosynthesis pathway

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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