7JG6
Cryo-EM structure of bedaquiline-free Mycobacterium smegmatis ATP synthase rotational state 2 (backbone model)
Summary for 7JG6
| Entry DOI | 10.2210/pdb7jg6/pdb |
| EMDB information | 22311 22312 22313 22314 22315 22316 22317 22318 22319 22320 22321 22322 |
| Descriptor | ATP synthase subunit alpha, ATP synthase subunit beta, ATP synthase gamma chain, ... (9 entities in total) |
| Functional Keywords | bedaquiline, sirturo, tmc207, t207910, atp synthase, mycobacteria, tuberculosis, translocase |
| Biological source | Mycolicibacterium smegmatis More |
| Total number of polymer chains | 20 |
| Total formula weight | 548232.84 |
| Authors | Guo, H.,Courbon, G.M.,Rubinstein, J.L. (deposition date: 2020-07-18, release date: 2020-08-19, Last modification date: 2024-03-06) |
| Primary citation | Guo, H.,Courbon, G.M.,Bueler, S.A.,Mai, J.,Liu, J.,Rubinstein, J.L. Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline. Nature, 589:143-147, 2021 Cited by PubMed Abstract: Tuberculosis-the world's leading cause of death by infectious disease-is increasingly resistant to current first-line antibiotics. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy conditions, allowing infections to remain dormant and decreasing their susceptibility to many antibiotics. Bedaquiline was developed in 2005 from a lead compound identified in a phenotypic screen against Mycobacterium smegmatis. This drug can sterilize even latent M. tuberculosis infections and has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Bedaquiline targets the mycobacterial ATP synthase, which is an essential enzyme in the obligate aerobic Mycobacterium genus, but how it binds the intact enzyme is unknown. Here we determined cryo-electron microscopy structures of M. smegmatis ATP synthase alone and in complex with bedaquiline. The drug-free structure suggests that hook-like extensions from the α-subunits prevent the enzyme from running in reverse, inhibiting ATP hydrolysis and preserving energy in hypoxic conditions. Bedaquiline binding induces large conformational changes in the ATP synthase, creating tight binding pockets at the interface of subunits a and c that explain the potency of this drug as an antibiotic for tuberculosis. PubMed: 33299175DOI: 10.1038/s41586-020-3004-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.7 Å) |
Structure validation
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