2I19

T. Brucei farnesyl diphosphate synthase complexed with bisphosphonate

2I19 の概要

• エントリーDOI: 10.2210/pdb2i19/pdb
• 分子名称: Farnesyl pyrophosphate synthase, MAGNESIUM ION, [2-(PYRIDIN-2-YLAMINO)ETHANE-1,1-DIYL]BIS(PHOSPHONIC ACID), ... (4 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: 89661.56

構造登録者

Cao, R.,Mao, J.,Gao, Y.,Robinson, H.,Odeh, S.,Goddard, A.,Oldfield, E. (登録日: 2006-08-13, 公開日: 2006-10-17, 最終更新日: 2023-08-30)

主引用文献

Mao, J.,Mukherjee, S.,Zhang, Y.,Cao, R.,Sanders, J.M.,Song, Y.,Zhang, Y.,Meints, G.A.,Gao, Y.G.,Mukkamala, D.,Hudock, M.P.,Oldfield, E.
Solid-state NMR, crystallographic, and computational investigation of bisphosphonates and farnesyl diphosphate synthase-bisphosphonate complexes.
J.Am.Chem.Soc., 128:14485-14497, 2006

PubMed Abstract: Bisphosphonates are a class of molecules in widespread use in treating bone resorption diseases and are also of interest as immunomodulators and anti-infectives. They function by inhibiting the enzyme farnesyl diphosphate synthase (FPPS), but the details of how these molecules bind are not fully understood. Here, we report the results of a solid-state (13)C, (15)N, and (31)P magic-angle sample spinning (MAS) NMR and quantum chemical investigation of several bisphosphonates, both as pure compounds and when bound to FPPS, to provide information about side-chain and phosphonate backbone protonation states when bound to the enzyme. We then used computational docking methods (with the charges assigned by NMR) to predict how several bisphosphonates bind to FPPS. Finally, we used X-ray crystallography to determine the structures of two potent bisphosphonate inhibitors, finding good agreement with the computational results, opening up the possibility of using the combination of NMR, quantum chemistry and molecular docking to facilitate the design of other, novel prenytransferase inhibitors.

PubMed: 17090032
DOI: 10.1021/ja061737c

実験手法

X-RAY DIFFRACTION (2.28 Å)