PDBsum entry 2o2y

Oxidoreductase

PDB id: 2o2y

Contents

Protein chains

290 a.a. *

Ligands

NAD ×4

TCL ×4

SO4

Metals

_CL ×4

Waters ×495

* Residue conservation analysis

PDB id:

2o2y

Name:

Oxidoreductase

Title:

The crystal structure of p. Falciparum enoyl acyl carrier protein reductase

Structure:

Enoyl-acyl carrier reductase. Chain: a, b, c, d. Fragment: residues 84-432. Synonym: enoyl-acp reductase. Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 36329. Strain: 3d7. Gene: fabi. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.20Å R-factor: 0.202 R-free: 0.246

Authors:

S.P.Muench,S.T.Prigge,R.Mcleod,J.B.Rafferty,M.J.Kirisits,C.W.Roberts, E.J.Mui,D.W.Rice

Key ref:

S.P.Muench et al. (2007). Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents. Acta Crystallogr D Biol Crystallogr, 63, 328-338. PubMed id: 17327670 DOI: 10.1107/S0907444906053625

Date:

30-Nov-06 Release date: 26-Dec-06

Protein chains

Q9BH77  (Q9BH77_PLAFA) -  Enoyl-ACP reductase from Plasmodium falciparum

Seq: 432 a.a.

Struc: 290 a.a.

Enzyme reactions

• Enzyme class: E.C.1.3.1.9 - enoyl-[acyl-carrier-protein] reductase (NADH).
• Reaction: a 2,3-saturated acyl-[ACP] + NAD⁺ = a (2E)-enoyl-[ACP] + NADH + H⁺

2,3-saturated acyl-[ACP] + NAD(+) (Bound ligand (Het Group name = NAD) corresponds exactly) = (2E)-enoyl-[ACP] + NADH + H(+)

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

Added reference

DOI no: 10.1107/S0907444906053625

Acta Crystallogr D Biol Crystallogr 63:328-338 (2007)

PubMed id: 17327670

Studies of Toxoplasma gondii and Plasmodium falciparum enoyl acyl carrier protein reductase and implications for the development of antiparasitic agents.

S.P.Muench, S.T.Prigge, R.McLeod, J.B.Rafferty, M.J.Kirisits, C.W.Roberts, E.J.Mui, D.W.Rice.

ABSTRACT

Recent studies have demonstrated that submicromolar concentrations of the biocide triclosan arrest the growth of the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii and inhibit the activity of the apicomplexan enoyl acyl carrier protein reductase (ENR). The crystal structures of T. gondii and P. falciparum ENR in complex with NAD(+) and triclosan and of T. gondii ENR in an apo form have been solved to 2.6, 2.2 and 2.8 A, respectively. The structures of T. gondii ENR have revealed that, as in its bacterial and plant homologues, a loop region which flanks the active site becomes ordered upon inhibitor binding, resulting in the slow tight binding of triclosan. In addition, the T. gondii ENR-triclosan complex reveals the folding of a hydrophilic insert common to the apicomplexan family that flanks the substrate-binding domain and is disordered in all other reported apicomplexan ENR structures. Structural comparison of the apicomplexan ENR structures with their bacterial and plant counterparts has revealed that although the active sites of the parasite enzymes are broadly similar to those of their bacterial counterparts, there are a number of important differences within the drug-binding pocket that reduce the packing interactions formed with several inhibitors in the apicomplexan ENR enzymes. Together with other significant structural differences, this provides a possible explanation of the lower affinity of the parasite ENR enzyme family for aminopyridine-based inhibitors, suggesting that an effective antiparasitic agent may well be distinct from equivalent antimicrobials.

Selected figure(s)

Figure 1.
Figure 1 The structural formulae of (a) triclosan and (b) (E)-N-methyl-N-(1-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-ylacrylamide (compound 29) produced using the program ISIS/Draw.

Figure 4.
Figure 4 2F[obs] - 1F[calc] electron-density maps for (a) PfENR and (b) TgENR contoured at 0.8 produced after initial rigid-body refinement in REFMAC5 (Murshudov et al., 1997[Murshudov, G., Vagin, A. & Dodson, E. (1997). Acta Cryst. D53, 240-255.]). Both NAD^+ and triclosan were omitted from the model during refinement, but are represented in stick format in order to show their unambiguous position in the initial electron-density maps. (c) Stereo diagram of the residues responsible for forming a hydrogen-bonding network to the NAD^+ cofactor in subunit A of TgENR. (d) Stereo diagram of the triclosan-binding site of subunit A of TgENR, with the active-site residues Tyr179, Tyr189, Lys197 and Phe243 labelled. (c) and (d) use the colour scheme yellow, red, blue, green and orange for carbon, oxygen, nitrogen, chlorine and phosphorus, respectively, and were produced in TURBO-FRODO (Roussel et al., 1990[Roussel, A., Fontecilla-Camps, J. C. & Cambillau, C. (1990). Acta Cryst. A46, C66-C67.]).

The above figures are reprinted by permission from the IUCr: Acta Crystallogr D Biol Crystallogr (2007, 63, 328-338) copyright 2007.

Figures were selected by an automated process.