2E9D

E. coli undecaprenyl pyrophosphate synthase in complex with BPH-676

Summary for 2E9D

• Entry DOI: 10.2210/pdb2e9d/pdb
• Related: 1X06 1X07 1X08 1X09 2E98 2E99 2E9A 2E9C
• Descriptor: Undecaprenyl pyrophosphate synthetase, [1-HYDROXY-2-(1,1':3',1''-TERPHENYL-3-YLOXY)ETHANE-1,1-DIYL]BIS(PHOSPHONIC ACID) (3 entities in total)
• Functional Keywords: cell wall, prenyltransferase, farnesyl pyrophosphate, bisphosphonate, antibiotic, transferase
• Biological source: Escherichia coli
• Total number of polymer chains: 2
• Total formula weight: 58313.20

Authors

Guo, R.T.,Cao, R.,Ko, T.P.,Liang, P.H.,Oldfield, E.,Wang, A.H.J. (deposition date: 2007-01-24, release date: 2007-06-12, Last modification date: 2023-10-25)

Primary citation

Guo, R.T.,Cao, R.,Liang, P.H.,Ko, T.P.,Chang, T.H.,Hudock, M.P.,Jeng, W.Y.,Chen, C.K.M.,Zhang, Y.,Song, Y.,Kuo, C.J.,Yin, F.,Oldfield, E.,Wang, A.H.J.
Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases
Proc.Natl.Acad.Sci.Usa, 104:10022-10027, 2007

PubMed Abstract: Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.

PubMed: 17535895
DOI: 10.1073/pnas.0702254104

Experimental method

X-RAY DIFFRACTION (2.5 Å)