2z7h
S. cerevisiae geranylgeranyl pyrophosphate synthase in complex with inhibitor BPH-210S. cerevisiae geranylgeranyl pyrophosphate synthase in complex with inhibitor BPH-210
Structural highlights
FunctionGGPPS_YEAST Catalyzes the trans-addition of the 3 molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate. Required for the membrane attachment of YPT1 and SEC4. May be involved in vesicle trafficking and protein sorting.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedWe 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 DeltaS is much smaller and DeltaH is approximately 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. (c) 2008 Wiley-Liss, Inc. Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases.,Cao R, Chen CK, Guo RT, Wang AH, Oldfield E Proteins. 2008 Apr 28;. PMID:18442135[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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