7F44

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

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7F44 の概要

• エントリーDOI: 10.2210/pdb7f44/pdb
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: fabi, nad, oxidoreductase
• 由来する生物種: Moraxella catarrhalis (strain BBH18)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31659.61

構造登録者

Katiki, M.,Neetu, N.,Pratap, S.,Kumar, P. (登録日: 2021-06-17, 公開日: 2022-06-22, 最終更新日: 2024-01-31)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.12 Å)