6TBB

Crystal structure of S. aureus FabI in complex with NADPH and kalimantacin A (batumin)

6TBB の概要

• エントリーDOI: 10.2210/pdb6tbb/pdb
• 関連するPDBエントリー: 6TBC
• 分子名称: Enoyl-[acyl-carrier-protein] reductase [NADPH], NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, Kalimantacin, ... (4 entities in total)
• 機能のキーワード: enoyl-[acyl carrier protein] reductase, fatty acid biosynthesis, rossmann fold, short-chain dehydrogenase/reductase, biosynthetic protein
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 238075.17

構造登録者

Fage, C.D.,Masschelein, J. (登録日: 2019-11-01, 公開日: 2020-04-01, 最終更新日: 2024-01-24)

主引用文献

Fage, C.D.,Lathouwers, T.,Vanmeert, M.,Gao, L.J.,Vrancken, K.,Lammens, E.M.,Weir, A.N.M.,Degroote, R.,Cuppens, H.,Kosol, S.,Simpson, T.J.,Crump, M.P.,Willis, C.L.,Herdewijn, P.,Lescrinier, E.,Lavigne, R.,Anne, J.,Masschelein, J.
The Kalimantacin Polyketide Antibiotics Inhibit Fatty Acid Biosynthesis in Staphylococcus aureus by Targeting the Enoyl-Acyl Carrier Protein Binding Site of FabI.
Angew.Chem.Int.Ed.Engl., 59:10549-10556, 2020

PubMed Abstract: The enoyl-acyl carrier protein reductase enzyme FabI is essential for fatty acid biosynthesis in Staphylococcus aureus and represents a promising target for the development of novel, urgently needed anti-staphylococcal agents. Here, we elucidate the mode of action of the kalimantacin antibiotics, a novel class of FabI inhibitors with clinically-relevant activity against multidrug-resistant S. aureus. By combining X-ray crystallography with molecular dynamics simulations, in vitro kinetic studies and chemical derivatization experiments, we characterize the interaction between the antibiotics and their target, and we demonstrate that the kalimantacins bind in a unique conformation that differs significantly from the binding mode of other known FabI inhibitors. We also investigate mechanisms of acquired resistance in S. aureus and identify key residues in FabI that stabilize the binding of the antibiotics. Our findings provide intriguing insights into the mode of action of a novel class of FabI inhibitors that will inspire future anti-staphylococcal drug development.

PubMed: 32208550
DOI: 10.1002/anie.201915407

実験手法

X-RAY DIFFRACTION (2.45 Å)