2p1c | pdb_00002p1c

T. Brucei Farnesyl Diphosphate Synthase Complexed with Bisphosphonate BPH-210

spinqualitylabelsall models 2p1c, resolution 2.45Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2p1c is a 2 chain structure with sequence from Trypanosoma brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, BME, GG3, MG Related: 2ewg, 2ogc, 2ogd, 2ogl Activity: Geranyltranstransferase, with EC number 2.5.1.10 Resources: FirstGlance, OCA, RCSB, PDBsum 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 PubMed 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Farnesyl diphosphate synthase

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