9S2U

1:1 complex of M.tuberculosis MmpL5 and M.smegmatis AcpM

9S2U の概要

• エントリーDOI: 10.2210/pdb9s2u/pdb
• 関連するPDBエントリー: 9RFU 9RGB
• EMDBエントリー: 54511
• 分子名称: Siderophore exporter MmpL5,Green fluorescent protein, Meromycolate extension acyl carrier protein (2 entities in total)
• 機能のキーワード: drug efflux, rnd transporter, tuberculosis, membrane protein
• 由来する生物種: Mycobacterium tuberculosis; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 119917.03

構造登録者

Fountain, A.J.,Luisi, B.F.,Ramakrishan, L. (登録日: 2025-07-22, 公開日: 2025-10-08)

主引用文献

Fountain, A.J.,Bohning, J.,McLaughlin, S.H.,Morgan, T.E.,Edelstein, P.H.,Troll, M.,Lamers, M.H.,Bharat, T.A.M.,Luisi, B.F.,Ramakrishnan, L.
Structural and functional analysis of the Mycobacterium tuberculosis MmpS5L5 efflux pump presages increased bedaquiline resistance.
Proc.Natl.Acad.Sci.USA, 122:e2516660122-e2516660122, 2025

PubMed Abstract: Bedaquiline, an antitubercular drug that targets ATP-synthase, is a key component of a new oral drug regimen that has revolutionized the treatment of multidrug-resistant tuberculosis. Clinical bedaquiline resistance in has rapidly emerged, primarily due to mutations in the transcriptional repressor that result in upregulation of the resistance-nodulation-division (RND) efflux pump MmpS5/MmpL5 (MmpS5L5). Here, to understand how MmpS5L5 effluxes bedaquiline, we determined the structure of the MmpS5L5 complex using cryo-electron microscopy, revealing a trimeric architecture distinct from the canonical tripartite RND efflux pumps of gram-negative bacteria. Structure prediction modeling in conjunction with functional genetic analysis indicates that it uses a periplasmic coiled-coil tube to transport molecules across the cell wall. Structure-guided genetic approaches identify MmpL5 mutations that alter bedaquiline transport; these mutations converge on a region in MmpL5 located in the lower portion of the periplasmic cavity, proximal to the outer leaflet of the inner membrane, suggesting a route for bedaquiline entry into the pump. While currently known clinical resistance to bedaquiline is due to pump upregulation, our findings that several MmpL5 variants increase bedaquiline efflux may presage the emergence of additional modes of clinical resistance.

PubMed: 40986343
DOI: 10.1073/pnas.2516660122

実験手法

ELECTRON MICROSCOPY (3.2 Å)