9RGB
M.tuberculosis MmpS5L5-acpM complex
Summary for 9RGB
| Entry DOI | 10.2210/pdb9rgb/pdb |
| Related | 9RFU |
| EMDB information | 53947 |
| Descriptor | Siderophore export accessory protein MmpS5, Siderophore exporter MmpL5,Green fluorescent protein, Meromycolate extension acyl carrier protein, ... (4 entities in total) |
| Functional Keywords | drug efflux, rnd transporter, tuberculosis, membrane protein |
| Biological source | Mycobacterium tuberculosis More |
| Total number of polymer chains | 9 |
| Total formula weight | 415882.19 |
| Authors | |
| Primary citation | 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 a pathway to increased bedaquiline resistance. Biorxiv, 2025 Cited by 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 multi drug 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 novel trimeric architecture distinct from the canonical tripartite RND efflux pumps of Gram-negative bacteria. Structure prediction modelling 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: 40667120DOI: 10.1101/2025.06.24.661325 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.2 Å) |
Structure validation
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