2Z4V

S. cerevisiae geranylgeranyl pyrophosphate synthase in complex with magnesium and GGPP (inhibitory site)

Summary for 2Z4V

• Entry DOI: 10.2210/pdb2z4v/pdb
• Related: 2Z4W 2Z4X 2Z4Y 2Z4Z 2Z50 2Z52
• Descriptor: Geranylgeranyl pyrophosphate synthetase, MAGNESIUM ION, GERANYLGERANYL DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: prenyltransferase, geranylgeranyl pyrophosphate, bisphosphonate, transferase
• Biological source: Saccharomyces cerevisiae (Baker's yeast)
• Cellular location: Cytoplasm (By similarity): Q12051
• Total number of polymer chains: 2
• Total formula weight: 79596.22

Authors

Chen, C.K.-M.,Guo, R.T.,Hudock, M.,Cao, R.,Oldfield, E.,Wang, A.H.-J. (deposition date: 2007-06-26, release date: 2008-07-01, Last modification date: 2023-11-01)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.86 Å)