Research ArticleBIOCHEMISTRY

Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline

Science Advances  08 May 2015:
Vol. 1, no. 4, e1500106
DOI: 10.1126/sciadv.1500106

You are currently viewing the abstract.

View Full Text

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.

Keywords
  • Tuberculosis (TB) antibiotics
  • F1Fo-ATP synthase rotor
  • c-ring
  • X-ray crystallography
  • membrane protein structure
  • Bedaquiline (BDQ)
  • SirturoTM
  • drug binding
  • inhibition mechanism

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

View Full Text

More Like This