PDBsum entry 2p1c

Transferase

PDB id: 2p1c

Contents

Protein chains

357 a.a. *

Ligands

ACT ×3

GG3 ×2

BME

Metals

_MG ×6

Waters ×306

* Residue conservation analysis

PDB id:

2p1c

Name:

Transferase

Title:

T. Brucei farnesyl diphosphate synthase complexed with bisphosphonate bph-210

Structure:

Farnesyl pyrophosphate synthase. Chain: a, b. Engineered: yes

Source:

Trypanosoma brucei. Organism_taxid: 5691. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.45Å R-factor: 0.266 R-free: 0.299

Authors:

R.Cao,Y.Gao,E.Oldfield

Key ref:

R.Cao et al. (2008). Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases. Proteins, 73, 431-439. PubMed id: 18442135 DOI: 10.1002/prot.22066

Date:

04-Mar-07 Release date: 04-Mar-08

Protein chains

Q86C09  (Q86C09_9TRYP) -  Farnesyl pyrophosphate synthase (Fragment) from Trypanosoma brucei

Seq: 367 a.a.

Struc: 357 a.a.

Enzyme reactions

• Enzyme class: E.C.2.5.1.10 - (2E,6E)-farnesyl diphosphate synthase.
• Pathway: Terpenoid biosynthesis
• Reaction: isopentenyl diphosphate + (2E)-geranyl diphosphate = (2E,6E)-farnesyl diphosphate + diphosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1002/prot.22066

Proteins 73:431-439 (2008)

PubMed id: 18442135

Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases.

R.Cao, C.K.Chen, R.T.Guo, A.H.Wang, E.Oldfield.

ABSTRACT

We report the X-ray crystallographic structures of the bisphosphonate N-[methyl(4-phenylbutyl)]-3-aminopropyl-1-hydroxy-1,1-bisphosphonate (BPH-210), a potent analog of pamidronate (Aredia), bound to farnesyl diphosphate synthase (FPPS) from Trypanosoma brucei as well as to geranylgeranyl diphosphate synthase from Saccharomyces cerevisiae. BPH-210 binds to FPPS, together with 3 Mg(2+), with its long, hydrophobic phenylbutyl side-chain being located in the same binding pocket that is occupied by allylic diphosphates and other bisphosphonates. Binding is overwhelmingly entropy driven, as determined by isothermal titration calorimetry. The structure is of interest since it explains the lack of potency of longer chain analogs against FPPS, since these would be expected to have a steric clash with an aromatic ring at the distal end of the binding site. Unlike shorter chain FPPS inhibitors, such as pamidronate, BPH-210 is also found to be a potent inhibitor of human geranylgeranyl diphosphate synthase. In this case, the bisphosphonate binds only to the GGPP product inhibitory site, with only 1 (chain A) or 0 (chain B) Mg(2+), and DeltaS is much smaller and DeltaH is approximately 6 k cal more negative than in the case of FPPS binding. Overall, these results are of general interest since they show that some bisphosphonates can bind to more than one trans-prenyl synthase enzyme which, in some cases, can be expected to enhance their overall activity in vitro and in vivo. Proteins 2008. (c) 2008 Wiley-Liss, Inc.

Selected figure(s)

Figure 1.
Figure 1. Structure and interactions in FPPS·BPH-210. (A) Schematic of T. brucei FPPS·BPH-210 dimer. (B) Ligplot interaction diagram show FPPS·BPH-210 interactions in chain A. (C) Ligplot interaction diagram of FPPS·BPH-210 interactions in chain B. (D) 2Fo-Fc electron density map for BPH-210 bound to FPPS in chain A (green contoured at 1 , red at 3 ). (E) 2Fo-Fc electron density map for BPH-210 in chain B (green contoured at 1 , red at 3 ).

Figure 3.
Figure 3. Partial sequence alignment of rat, human, chicken, T. brucei, T. gondi, FPPSs. The first DDXXD repeat is shaded in red, the two aromatic amino-acids 4 and 5 residues upstream of the first DDXXD repeat (PhePhe in rat, human and chicken, HisTyr in T. brucei) that control to a significant extent, product specificity, and which are likely to interact with the phenyl ring in BPH-210, are shown in green.

The above figures are reprinted from an Open Access publication published by John Wiley & Sons, Inc.: Proteins (2008, 73, 431-439) copyright 2008.

Figures were selected by an automated process.