PDBsum entry 1vrw

Oxidoreductase

PDB id: 1vrw

Contents

Protein chains

289 a.a. *

Ligands

NAI ×2

* Residue conservation analysis

PDB id:

1vrw

Name:

Oxidoreductase

Title:

Crystal structure analysis of plasmodium falciparum enoyl-acyl- carrier-protein reductase with nadh

Structure:

Enoyl-acyl carrier reductase. Chain: a, b. Synonym: enoyl-acp-reductase. Engineered: yes

Source:

Plasmodium falciparum. Malaria parasite p. Falciparum. Organism_taxid: 5833. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Tetramer (from PQS)

Resolution:

2.40Å R-factor: 0.176 R-free: 0.224

Authors:

R.Perozzo,M.Kuo,A.S.Sidhu,J.T.Valiyaveettil,R.Bittman,W.R.Jacobs Jr., D.A.Fidock,J.C.Sacchettini

Key ref:

R.Perozzo et al. (2002). Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. J Biol Chem, 277, 13106-13114. PubMed id: 11792710 DOI: 10.1074/jbc.M112000200

Date:

30-Jun-05 Release date: 05-Jul-05

Supersedes:

1nhd

Protein chains

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

Seq: 432 a.a.

Struc: 289 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 = NAI) corresponds exactly) = (2E)-enoyl-[ACP] + NADH + H(+)

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

Added reference

DOI no: 10.1074/jbc.M112000200

J Biol Chem 277:13106-13114 (2002)

PubMed id: 11792710

Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase.

R.Perozzo, M.Kuo, A.S.Sidhu, J.T.Valiyaveettil, R.Bittman, W.R.Jacobs, D.A.Fidock, J.C.Sacchettini.

ABSTRACT

The human malaria parasite Plasmodium falciparum synthesizes fatty acids using a type II pathway that is absent in humans. The final step in fatty acid elongation is catalyzed by enoyl acyl carrier protein reductase, a validated antimicrobial drug target. Here, we report the cloning and expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50-kDa protein (PfENR) predicted to target to the unique parasite apicoplast. Purified PfENR was crystallized, and its structure resolved as a binary complex with NADH, a ternary complex with triclosan and NAD(+), and as ternary complexes bound to the triclosan analogs 1 and 2 with NADH. Novel structural features were identified in the PfENR binding loop region that most closely resembled bacterial homologs; elsewhere the protein was similar to ENR from the plant Brassica napus (root mean square for Calphas, 0.30 A). Triclosan and its analogs 1 and 2 killed multidrug-resistant strains of intra-erythrocytic P. falciparum parasites at sub to low micromolar concentrations in vitro. These data define the structural basis of triclosan binding to PfENR and will facilitate structure-based optimization of PfENR inhibitors.

Selected figure(s)

Figure 2.
Fig. 2. Tertiary structure of PfENR. a, representation of subunit B of the PfENR tetramer with the cofactor NADH and inhibitor triclosan bound to their active sites. Helices are shown in gold, the -strands in green, NADH and triclosan are colored by atom type. The tertiary structure shows the Rossmann fold typical of dinucleotide-binding enzymes (43). The chain break visible at the top of the inhibitor binding site is due to the PfENR substrate binding loop that was not resolved in the crystal structures. b, front view of the PfENR tetramer, in which each subunit is represented as a differently colored tube. The bound NADH is colored by atom type. Three perpendicular 2-fold symmetry axes intersect in the center, creating a molecule of internal 222 symmetry.

Figure 4.
Fig. 4. Structural details of the substrate/inhibitor binding site. a, stereo view of the 2F[o] F[c] electron density map contoured at 1 for bound analog 2 and NADH cofactor. Shown are residues 277 and 216-221. b, stereo view of the three superimposed PfENR·inhibitor complexes. Residues involved in the formation of the binding pocket are shown. The most important amino acids for interactions are labeled. Triclosan is shown in red, 1 in blue, and 2 in green. The corresponding cofactor of each inhibitor complex is colored accordingly. Hydrogen bonds with Tyr277 and the 2'-hydroxyl group of the nicotinamide ribose, as well as three additional hydrogen bonds mediated through the hydroxyl group of the naphthalene ring of 2 are shown as yellow dotted lines. The binding mode of triclosan, 1, and 2 showed the same stacking interactions to the nicotinamide ring of the cofactor with respect to ring A. Inhibitor 2 also exhibited three additional hydrogen bonds mediated through the hydroxyl group of the naphthalene ring that could interact with the side-chain nitrogen of Asn218 and the main-chain oxygen and nitrogen of Ala^219.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2002, 277, 13106-13114) copyright 2002.

Figures were selected by an automated process.