3EFQ

T. Brucei Farnesyl Diphosphate Synthase Complexed with Bisphosphonate BPH-714

3EFQ の概要

• エントリーDOI: 10.2210/pdb3efq/pdb
• 分子名称: Farnesyl pyrophosphate synthase, MAGNESIUM ION, 1-(2,2-diphosphonoethyl)-3-(octyloxy)pyridinium, ... (4 entities in total)
• 機能のキーワード: protein-bisphosphonate complex, isoprene biosynthesis, 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: 89889.97

構造登録者

Cao, R.,Gao, Y.,Robinson, H.,Oldfield, E. (登録日: 2008-09-09, 公開日: 2009-05-05, 最終更新日: 2024-02-21)

主引用文献

Zhang, Y.,Cao, R.,Yin, F.,Hudock, M.P.,Guo, R.T.,Krysiak, K.,Mukherjee, S.,Gao, Y.G.,Robinson, H.,Song, Y.,No, J.H.,Bergan, K.,Leon, A.,Cass, L.,Goddard, A.,Chang, T.K.,Lin, F.Y.,Van Beek, E.,Papapoulos, S.,Wang, A.H.,Kubo, T.,Ochi, M.,Mukkamala, D.,Oldfield, E.
Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation.
J.Am.Chem.Soc., 131:5153-5162, 2009

PubMed Abstract: Considerable effort has focused on the development of selective protein farnesyl transferase (FTase) and protein geranylgeranyl transferase (GGTase) inhibitors as cancer chemotherapeutics. Here, we report a new strategy for anticancer therapeutic agents involving inhibition of farnesyl diphosphate synthase (FPPS) and geranylgeranyl diphosphate synthase (GGPPS), the two enzymes upstream of FTase and GGTase, by lipophilic bisphosphonates. Due to dual site targeting and decreased polarity, the compounds have activities far greater than do current bisphosphonate drugs in inhibiting tumor cell growth and invasiveness, both in vitro and in vivo. We explore how these compounds inhibit cell growth and how cell activity can be predicted based on enzyme inhibition data, and using X-ray diffraction, solid state NMR, and isothermal titration calorimetry, we show how these compounds bind to FPPS and/or GGPPS.

PubMed: 19309137
DOI: 10.1021/ja808285e

実験手法

X-RAY DIFFRACTION (2 Å)