2Z52

S. cerevisiae geranylgeranyl pyrophosphate synthase in complex with magnesium and BPH-23

2Z52 の概要

• エントリーDOI: 10.2210/pdb2z52/pdb
• 関連するPDBエントリー: 2Z4V 2Z4W 2Z4X 2Z4Y 2Z4Z 2Z50
• 分子名称: Geranylgeranyl pyrophosphate synthetase, MAGNESIUM ION, (1-HYDROXYDODECANE-1,1-DIYL)BIS(PHOSPHONIC ACID), ... (4 entities in total)
• 機能のキーワード: prenyltransferase, geranylgeranyl pyrophosphate, bisphosphonate, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Saccharomyces cerevisiae (Baker's yeast)
• 細胞内の位置: Cytoplasm (By similarity): Q12051
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 79436.54

構造登録者

Guo, R.T.,Chen, C.K.-M.,Hudock, M.,Cao, R.,Oldfield, E.,Wang, A.H.-J. (登録日: 2007-06-26, 公開日: 2008-07-01, 最終更新日: 2023-11-01)

主引用文献

Chen, C.K.-M.,Hudock, M.P.,Zhang, Y.,Guo, R.-T.,Cao, R.,No, J.H.,Liang, P.-H.,Ko, T.-P.,Chang, T.-H.,Chang, S.-C.,Song, Y.,Axelson, J.,Kumar, A.,Wang, A.H.-J.,Oldfield, E.
Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation
J.Med.Chem., 51:5594-5607, 2008

PubMed Abstract: We report the X-ray structures of several bisphosphonate inhibitors of geranylgeranyl diphosphate synthase, a target for anticancer drugs. Bisphosphonates containing unbranched side chains bind to either the farnesyl diphosphate (FPP) substrate site, the geranylgeranyl diphosphate (GGPP) product site, and in one case, both sites, with the bisphosphonate moiety interacting with 3 Mg (2+) that occupy the same position as found in FPP synthase. However, each of three "V-shaped" bisphosphonates bind to both the FPP and GGPP sites. Using the Glide program, we reproduced the binding modes of 10 bisphosphonates with an rms error of 1.3 A. Activities of the bisphosphonates in GGPPS inhibition were predicted with an overall error of 2x by using a comparative molecular similarity analysis based on a docked-structure alignment. These results show that some GGPPS inhibitors can occupy both substrate and product site and that binding modes as well as activity can be accurately predicted, facilitating the further development of GGPPS inhibitors as anticancer agents.

PubMed: 18800762
DOI: 10.1021/jm800325y

実験手法

X-RAY DIFFRACTION (2.13 Å)