Tuberculosis (TB), the leading cause of death by infectious disease worldwide, is increasingly resistant to first line antibiotics. Developed from a screen against Mycobacterium smegmatis, bedaquiline can sterilize even latent M. tuberculosis infections that may otherwise persist for decades and has become a cornerstone of treatment for multidrug resistant and extensively-drug resistant TB. Bedaquiline targets mycobacterial ATP synthase, an essential enzyme in the obligate aerobic Mycobacterium genus. However, how the drug binds the intact enzyme is unknown. We determined the structure of M. smegmatis ATP synthase with and without bedaquiline. The drug-free structure reveals hook-like extensions from the enzyme's α subunits that inhibit ATP hydrolysis in low-energy conditions, such as during latent infections. Bedaquiline binding induces global conformational changes in ATP synthase, creating tight binding pockets at the interface of subunits a and c. These binding sites explain the drug's structure-activity relationship and its potency as an antibiotic for TB. ### Competing Interest Statement The authors have declared no competing interest.
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