2P1C

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

2P1C の概要

• エントリーDOI: 10.2210/pdb2p1c/pdb
• 関連するPDBエントリー: 2EWG 2OGC 2OGD 2OGL
• 分子名称: Farnesyl pyrophosphate synthase, MAGNESIUM ION, ACETATE ION, ... (6 entities in total)
• 機能のキーワード: protein-bisphosphonate complex, transferase
• 由来する生物種: Trypanosoma brucei
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 90115.17

構造登録者

Cao, R.,Gao, Y.,Oldfield, E. (登録日: 2007-03-04, 公開日: 2008-03-04, 最終更新日: 2023-08-30)

主引用文献

Cao, R.,Chen, C.K.,Guo, R.T.,Wang, A.H.,Oldfield, E.
Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases.
Proteins, 73:431-439, 2008

PubMed 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) 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.

PubMed: 18442135
DOI: 10.1002/prot.22066

実験手法

X-RAY DIFFRACTION (2.45 Å)