PDBsum entry 2z6j

Oxidoreductase

PDB id: 2z6j

Contents

Protein chains

307 a.a. *

Ligands

FMN ×2

TUI ×2

MPD

Metals

_CA ×4

Waters ×72

* Residue conservation analysis

PDB id:

2z6j

Name:

Oxidoreductase

Title:

Crystal structure of s. Pneumoniae enoyl-acyl carrier protein reductase (fabk) in complex with an inhibitor

Structure:

Trans-2-enoyl-acp reductase ii. Chain: a, b. Synonym: enoyl-acyl-carrier-protein, reductase. Engineered: yes

Source:

Streptococcus pneumoniae. Organism_taxid: 1313. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.30Å R-factor: 0.252 R-free: 0.306

Authors:

J.Saito,M.Yamada,T.Watanabe,Y.Takeuchi

Key ref:

J.Saito et al. (2008). Crystal structure of enoyl-acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor. Protein Sci, 17, 691-699. PubMed id: 18305197 DOI: 10.1110/ps.073288808

Date:

01-Aug-07 Release date: 01-Apr-08

Protein chains

Q9FBC5  (Q9FBC5_STREE) -  Enoyl-ACP reductase II from Streptococcus pneumoniae

Seq: 324 a.a.

Struc: 307 a.a.

Enzyme reactions

• Enzyme class 1: E.C.1.13.12.16 - nitronate monooxygenase.
• Reaction: ethylnitronate + O2 = chemical entity + acetaldehyde + nitrite + H⁺
• Cofactor: FMN

FMN (Bound ligand (Het Group name = FMN) corresponds exactly)

• Enzyme class 2: E.C.1.3.-.-

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

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

reference

DOI no: 10.1110/ps.073288808

Protein Sci 17:691-699 (2008)

PubMed id: 18305197

Crystal structure of enoyl-acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor.

J.Saito, M.Yamada, T.Watanabe, M.Iida, H.Kitagawa, S.Takahata, T.Ozawa, Y.Takeuchi, F.Ohsawa.

ABSTRACT

Enoyl-acyl carrier protein (ACP) reductases are critical for bacterial type II fatty acid biosynthesis and thus are attractive targets for developing novel antibiotics. We determined the crystal structure of enoyl-ACP reductase (FabK) from Streptococcus pneumoniae at 1.7 A resolution. There was one dimer per asymmetric unit. Each subunit formed a triose phosphate isomerase (TIM) barrel structure, and flavin mononucleotide (FMN) was bound as a cofactor in the active site. The overall structure was similar to the enoyl-ACP reductase (ER) of fungal fatty acid synthase and to 2-nitropropane dioxygenase (2-ND) from Pseudomonas aeruginosa, although there were some differences among these structures. We determined the crystal structure of FabK in complex with a phenylimidazole derivative inhibitor to envision the binding site interactions. The crystal structure reveals that the inhibitor binds to a hydrophobic pocket in the active site of FabK, and this is accompanied by induced-fit movements of two loop regions. The thiazole ring and part of the ureido moiety of the inhibitor are involved in a face-to-face pi-pi stacking interaction with the isoalloxazine ring of FMN. The side-chain conformation of the proposed catalytic residue, His144, changes upon complex formation. Lineweaver-Burk plots indicate that the inhibitor binds competitively with respect to NADH, and uncompetitively with respect to crotonoyl coenzyme A. We propose that the primary basis of the inhibitory activity is competition with NADH for binding to FabK, which is the first step of the two-step ping-pong catalytic mechanism.

Selected figure(s)

Figure 1.
Chemical structures of FabK inhibitors, AG205 and compound 1. Dashed lines enclose similar components of the two compounds.

Figure 6.
(A) Superposition of the active sites of S. pneumoniae FabK --compound 1 complex (green) with fungal ER --NADP^+ complex (cyan). FMN, compound 1, NADP^+, and side chains of the proposed catalytic histidine residues are shown as stick models. Non-carbon atoms are colored according to atom type. (B) Superposition of the active sites of S. pneumoniae FabK --compound 1 complex (green) with P. aeruginosa 2-ND in complex with the substrate, 2-nitropropane (pink). (C) Two-step ping-pong catalytic mechanism of FabK. FabK --FMN represents the oxidized form of the enzyme, and FabK --FMNH[2] ^[minus sign] represents the reduced form. R represents the CH[3](CH[2])[n][minus sign] (n = 1 [minus sign] 12). Compound 1 is considered to be a competitive inhibitor for the first step of the reaction.

The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (2008, 17, 691-699) copyright 2008.

Figures were selected by an automated process.