Structure of mycobacterial ATP synthase bound to the tuberculosis drug bedaquiline
| Autor: | Jun Liu, Stephanie A. Bueler, Gautier M. Courbon, John L. Rubinstein, Hui Guo, Juntao Mai |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Tuberculosis Rotation Mycobacterium smegmatis Antitubercular Agents Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Adenosine Triphosphate ATP hydrolysis medicine Diarylquinolines 030304 developmental biology chemistry.chemical_classification 0303 health sciences Multidisciplinary biology ATP synthase 030306 microbiology Chemistry Hydrolysis Cryoelectron Microscopy biology.organism_classification medicine.disease ATP Synthetase Complexes Enzyme Biochemistry biology.protein Bedaquiline Mycobacterium |
| Zdroj: | Nature. 589:143-147 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/s41586-020-3004-3 |
| Popis: | Tuberculosis—the world’s leading cause of death by infectious disease—is increasingly resistant to current first-line antibiotics1. The bacterium Mycobacterium tuberculosis (which causes tuberculosis) can survive low-energy conditions, allowing infections to remain dormant and decreasing their susceptibility to many antibiotics2. Bedaquiline was developed in 2005 from a lead compound identified in a phenotypic screen against Mycobacterium smegmatis3. This drug can sterilize even latent M. tuberculosis infections4 and has become a cornerstone of treatment for multidrug-resistant and extensively drug-resistant tuberculosis1,5,6. Bedaquiline targets the mycobacterial ATP synthase3, which is an essential enzyme in the obligate aerobic Mycobacterium genus3,7, 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. Structures of Mycobacterium smegmatis ATP synthase provide insights into how the enzyme conserves energy by autoinhibition of ATP hydrolysis and the mechanism of action of bedaquiline, a drug used in treatment of multidrug-resistant tuberculosis. |
| Databáze: | OpenAIRE |
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