7F44

Crystal structure of Moraxella catarrhalis enoyl-ACP-reductase (FabI) in complex with the cofactor NAD

Replaces:  6IWL

Summary for 7F44

• Entry DOI: 10.2210/pdb7f44/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: fabi, nad, oxidoreductase
• Biological source: Moraxella catarrhalis (strain BBH18)
• Total number of polymer chains: 1
• Total formula weight: 31659.61

Authors

Katiki, M.,Neetu, N.,Pratap, S.,Kumar, P. (deposition date: 2021-06-17, release date: 2022-06-22, Last modification date: 2024-01-31)

Primary citation

Katiki, M.,Neetu, N.,Pratap, S.,Kumar, P.
Biochemical and structural basis for Moraxella catarrhalis enoyl-acyl carrier protein reductase (FabI) inhibition by triclosan and estradiol.
Biochimie, 198:8-22, 2022

PubMed Abstract: The enoyl-acyl carrier protein reductase (ENR) is an established drug target and catalyzes the last reduction step of the fatty acid elongation cycle. Here, we report the crystal structures of FabI from Moraxella catarrhalis (McFabI) in the apo form, binary complex with NAD+ and ternary complex with NAD  -triclosan (TCL) determined at 2.36, 2.12 and 2.22 Å resolutions, respectively. The comparative study of these three structures revealed three different conformational states for the substrate-binding loop (SBL), including an unstructured intermediate, a structured intermediate and a closed conformation in the apo, binary and ternary complex forms, respectively; indicating the flexibility of SBL during the ligand binding. Virtual screening has suggested that estradiol cypionate may be a potential inhibitor of McFabI. Subsequently, estradiol (EST), the natural form of estradiol cypionate, was assessed for its FabI-binding and -inhibition properties. In vitro studies demonstrated that TCL and EST bind to McFabI with high affinity (K = 0.038 ± 0.004 and 5 ± 0.06 μM respectively) and inhibit its activity (K = 62.93 ± 3.95 nM and 25.97 ± 1.93 μM respectively) and suppress the growth of M. catarrhalis. These findings reveal that TCL and EST inhibit the McFabI activity and thereby affect cell growth. This study suggests that estradiol may be exploited as a novel scaffold for the designing and development of more potential FabI inhibitors.

PubMed: 35276316
DOI: 10.1016/j.biochi.2022.02.008

Experimental method

X-RAY DIFFRACTION (2.12 Å)