7LO7

NorA in complex with Fab25

7LO7 の概要

• エントリーDOI: 10.2210/pdb7lo7/pdb
• EMDBエントリー: 23463
• 分子名称: Quinolone resistance protein NorA, Fab25 Heavy Chain, Fab25 Light Chain (3 entities in total)
• 機能のキーワード: efflux pump, antibiotic resistance, transport protein
• 由来する生物種: Staphylococcus aureus; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 96363.79

構造登録者

Brawley, D.N.,Sauer, D.B.,Song, J.M.,Koide, A.,Koide, S.,Traaseth, N.J.,Wang, D.N. (登録日: 2021-02-09, 公開日: 2022-04-20, 最終更新日: 2025-05-28)

主引用文献

Brawley, D.N.,Sauer, D.B.,Li, J.,Zheng, X.,Koide, A.,Jedhe, G.S.,Suwatthee, T.,Song, J.,Liu, Z.,Arora, P.S.,Koide, S.,Torres, V.J.,Wang, D.N.,Traaseth, N.J.
Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus.
Nat.Chem.Biol., 18:706-712, 2022

PubMed Abstract: Membrane protein efflux pumps confer antibiotic resistance by extruding structurally distinct compounds and lowering their intracellular concentration. Yet, there are no clinically approved drugs to inhibit efflux pumps, which would potentiate the efficacy of existing antibiotics rendered ineffective by drug efflux. Here we identified synthetic antigen-binding fragments (Fabs) that inhibit the quinolone transporter NorA from methicillin-resistant Staphylococcus aureus (MRSA). Structures of two NorA-Fab complexes determined using cryo-electron microscopy reveal a Fab loop deeply inserted in the substrate-binding pocket of NorA. An arginine residue on this loop interacts with two neighboring aspartate and glutamate residues essential for NorA-mediated antibiotic resistance in MRSA. Peptide mimics of the Fab loop inhibit NorA with submicromolar potency and ablate MRSA growth in combination with the antibiotic norfloxacin. These findings establish a class of peptide inhibitors that block antibiotic efflux in MRSA by targeting indispensable residues in NorA without the need for membrane permeability.

PubMed: 35361990
DOI: 10.1038/s41589-022-00994-9

実験手法

ELECTRON MICROSCOPY (3.74 Å)