title: Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline.
abstract: Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9 ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring's ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tuberculosis and other bacterial pathogens.
authors.affiliation: Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, 60438 Frankfurt am Main, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Preiss
authors.affiliation: Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany.
authors.forename: Julian D
authors.initials: JD
authors.lastname: Langer
authors.affiliation: Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, 60438 Frankfurt am Main, Germany.
authors.forename: Özkan
authors.initials: Ö
authors.lastname: Yildiz
authors.affiliation: Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, 60438 Frankfurt am Main, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: Eckhardt-Strelau
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, Campus de Maigremont-BP615, 27106 Val de Reuil Cedex, France.
authors.forename: Jérôme E G
authors.initials: JE
authors.lastname: Guillemont
authors.affiliation: Department of Respiratory Infections, Infectious Diseases and Vaccines Group, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, B-2340 Beerse, Belgium.
authors.forename: Anil
authors.initials: A
authors.lastname: Koul
authors.affiliation: Department of Structural Biology, Max Planck Institute of Biophysics, Max-von-Laue-Straße 3, 60438 Frankfurt am Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meier
keywords: Bedaquiline (BDQ); F1Fo-ATP synthase rotor; SirturoTM; Tuberculosis (TB) antibiotics; X-ray crystallography; c-ring; drug binding; inhibition mechanism; membrane protein structure