6VKT

Cryo-electron microscopy structures of a gonococcal multidrug efflux pump illuminate a mechanism of erythromycin drug recognition

6VKT の概要

• エントリーDOI: 10.2210/pdb6vkt/pdb
• EMDBエントリー: 21229
• 分子名称: Efflux pump membrane transporter, PHOSPHATIDYLETHANOLAMINE, ERYTHROMYCIN A (3 entities in total)
• 機能のキーワード: efflux, pump, erythromycin, membrane protein
• 由来する生物種: Neisseria gonorrhoeae
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 352548.73

構造登録者

Lyu, M.,Moseng, M.A. (登録日: 2020-01-22, 公開日: 2020-07-01, 最終更新日: 2024-03-06)

主引用文献

Lyu, M.,Moseng, M.A.,Reimche, J.L.,Holley, C.L.,Dhulipala, V.,Su, C.C.,Shafer, W.M.,Yu, E.W.
Cryo-EM Structures of a Gonococcal Multidrug Efflux Pump Illuminate a Mechanism of Drug Recognition and Resistance.
Mbio, 11:-, 2020

PubMed Abstract: is an obligate human pathogen and causative agent of the sexually transmitted infection (STI) gonorrhea. The most predominant and clinically important multidrug efflux system in is the ultiple ransferrable esistance (Mtr) pump, which mediates resistance to a number of different classes of structurally diverse antimicrobial agents, including clinically used antibiotics (e.g., β-lactams and macrolides), dyes, detergents and host-derived antimicrobials (e.g., cationic antimicrobial peptides and bile salts). Recently, it has been found that gonococci bearing mosaic-like sequences within the gene can result in amino acid changes that increase the MtrD multidrug efflux pump activity, probably by influencing antimicrobial recognition and/or extrusion to elevate the level of antibiotic resistance. Here, we report drug-bound solution structures of the MtrD multidrug efflux pump carrying a mosaic-like sequence using single-particle cryo-electron microscopy, with the antibiotics bound deeply inside the periplasmic domain of the pump. Through this structural approach coupled with genetic studies, we identify critical amino acids that are important for drug resistance and propose a mechanism for proton translocation. has become a highly antimicrobial-resistant Gram-negative pathogen. Multidrug efflux is a major mechanism that uses to counteract the action of multiple classes of antibiotics. It appears that gonococci bearing mosaic-like sequences within the gene , encoding the most predominant and clinically important transporter of any gonococcal multidrug efflux pump, significantly elevate drug resistance and enhance transport function. Here, we report cryo-electron microscopy (EM) structures of MtrD carrying a mosaic-like sequence that allow us to understand the mechanism of drug recognition. Our work will ultimately inform structure-guided drug design for inhibiting these critical multidrug efflux pumps.

PubMed: 32457251
DOI: 10.1128/mBio.00996-20

実験手法

ELECTRON MICROSCOPY (2.72 Å)