Premium
Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases
Author(s) -
Cao Rong,
Chen Cammy K.M.,
Guo ReyTing,
Wang Andrew H.J.,
Oldfield Eric
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22066
Subject(s) - farnesyl diphosphate synthase , chemistry , farnesyl pyrophosphate , stereochemistry , mevalonate pathway , isothermal titration calorimetry , bisphosphonate , atp synthase , steric effects , prenylation , binding site , mevalonic acid , biochemistry , enzyme , biosynthesis , biology , osteoporosis , endocrinology
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) Mg 2+ , and Δ S is much smaller and Δ H 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 . Proteins 2008. © 2008 Wiley‐Liss, Inc.