Imperial College London
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ProfessorThomasMeier

Faculty of Natural Sciences, Department of Life Sciences

Visiting Professor
 
 
 
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Contact

 

t.meier Website

 
 
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Location

 

501Sir Ernst Chain BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Preiss:2015:10.1126/sciadv.1500106,
author = {Preiss, L and Langer, JD and Yildiz, O and Eckhardt-Strelau, L and Guillemont, JEG and Koul, A and Meier, T},
doi = {10.1126/sciadv.1500106},
journal = {Science Advances},
pages = {e1500106--e1500106},
title = {Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline},
url = {http://dx.doi.org/10.1126/sciadv.1500106},
volume = {1},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Preiss,L
AU  - Langer,JD
AU  - Yildiz,O
AU  - Eckhardt-Strelau,L
AU  - Guillemont,JEG
AU  - Koul,A
AU  - Meier,T
DO  - 10.1126/sciadv.1500106
EP  - 1500106
PY  - 2015///
SN  - 2375-2548
SP  - 1500106
TI  - Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline
T2  - Science Advances
UR  - http://dx.doi.org/10.1126/sciadv.1500106
UR  - http://hdl.handle.net/10044/1/59223
VL  - 1
ER  -
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