2O1O

Cryptosporidium parvum putative polyprenyl pyrophosphate synthase (cgd4_2550) in complex with risedronate.

2O1O の概要

• エントリーDOI: 10.2210/pdb2o1o/pdb
• 関連するPDBエントリー: 2HER
• 分子名称: Putative farnesyl pyrophosphate synthase, MAGNESIUM ION, 1-HYDROXY-2-(3-PYRIDINYL)ETHYLIDENE BIS-PHOSPHONIC ACID, ... (4 entities in total)
• 機能のキーワード: putative polyprenyl pyrophosphate synthase, structural genomics, structural genomics consortium, sgc, unknown function
• 由来する生物種: Cryptosporidium parvum
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 86658.16

構造登録者

Chruszcz, M.,Artz, J.D.,Dong, A.,Dunford, J.,Lew, J.,Zhao, Y.,Kozieradski, I.,Kavanaugh, K.L.,Oppermann, U.,Sundstrom, M.,Weigelt, J.,Edwards, A.M.,Arrowsmith, C.H.,Bochkarev, A.,Hui, R.,Minor, W.,Structural Genomics Consortium (SGC) (登録日: 2006-11-29, 公開日: 2006-12-12, 最終更新日: 2023-08-30)

主引用文献

Artz, J.D.,Dunford, J.E.,Arrowood, M.J.,Dong, A.,Chruszcz, M.,Kavanagh, K.L.,Minor, W.,Russell, R.G.,Ebetino, F.H.,Oppermann, U.,Hui, R.
Targeting a uniquely nonspecific prenyl synthase with bisphosphonates to combat cryptosporidiosis
Chem.Biol., 15:1296-1306, 2008

PubMed Abstract: Cryptosporidiosis is a neglected disease without a wholly effective drug. We present a study demonstrating nitrogen-containing bisphosphonates (N-BPs) to be capable of inhibiting Cryptosporidium parvum at low micromolar concentrations in infected MDCK cells. Predictably, the mechanism of action is based on inhibition of biosynthesis of isoprenoids but the target enzyme is unexpectedly a distinctive C. parvum enzyme dubbed nonspecific polyprenyl pyrophosphate synthase (CpNPPPS). This enzyme produces various isoprenoid products larger than FPP and is inhibited by N-BPs at subnanomolar concentrations. It is part of an isoprenoid pathway in Cryptosporidium distinctly different from other organisms. The proposed mechanism of action is corroborated by crystal structures of the enzyme with risedronate and zoledronate bound showing how this enzyme's unique chain length determinant region enables it to accommodate larger substrates and products. These results, combined with existing data on their clinical use, demonstrate that N-BPs are very promising anticryptosporidial drug candidates.

PubMed: 19101474
DOI: 10.1016/j.chembiol.2008.10.017

実験手法

X-RAY DIFFRACTION (2.42 Å)