PDBsum entry 2e90

Transferase

PDB id: 2e90

Contents

Protein chains

299 a.a.

Ligands

PPV ×2

FPP ×2

Metals

_MG ×4

Waters ×318

References listed in PDB file

Key reference

Title

Bisphosphonates target multiple sites in both cis- And trans-Prenyltransferases.

Authors

R.T.Guo, R.Cao, P.H.Liang, T.P.Ko, T.H.Chang, M.P.Hudock, W.Y.Jeng, C.K.Chen, Y.Zhang, Y.Song, C.J.Kuo, F.Yin, E.Oldfield, A.H.Wang.

Ref.

Proc Natl Acad Sci U S A, 2007, 104, 10022-10027. [DOI no: 10.1073/pnas.0702254104]

PubMed id

17535895

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.

Figure 2.
Fig. 2. Bisphosphonates and GGPPS structures. (A) Structures of bisphosphonates investigated as GGPPS inhibitors. (B) GGPPS structure containing zoledronate (PDB ID code 2E91) showing dimer structure. (C) Stereoview of minodronate bound to GGPPS (PDB ID code 2E92). (D) Stereoview of zoledronate/GGPPS (PDB ID code 2E91) superimposed on zoledronate/IPP/FPPS structure (PDB ID code 2F8C).

Figure 3.
Fig. 3. Structures of hydrophobic bisphosphonates bound to GGPPS. (A) Stereoview of BPH-675 (PDB ID code 2E95). (B) Electron density (green contoured at 1 , red at 3 ) for the two BPH-629 conformers (PDB ID code 2E93). (C) Structure of BPH-629 bound to GGPPS (monomer A model is shown).