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Title: Variations of subunit ε of the Mycobacterium tuberculosis F 1FO ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207
Authors: Biuković, G.
Basak, S.
Manimekalai, M.S.S.
Rishikesan, S.
Roessle, M.
Dick, T. 
Rao, S.P.S.
Hunke, C.
Grüber, G.
Issue Date: Jan-2013
Citation: Biuković, G., Basak, S., Manimekalai, M.S.S., Rishikesan, S., Roessle, M., Dick, T., Rao, S.P.S., Hunke, C., Grüber, G. (2013-01). Variations of subunit ε of the Mycobacterium tuberculosis F 1FO ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207. Antimicrobial Agents and Chemotherapy 57 (1) : 168-176. ScholarBank@NUS Repository.
Abstract: The subunit ε of bacterial F1FO ATP synthases plays an important regulatory role in coupling and catalysis via conformational transitions of its C-terminal domain. Here we present the first low-resolution solution structure of ε of Mycobacterium tuberculosis (Mtε) F 1FO ATP synthase and the nuclear magnetic resonance (NMR) structure of its C-terminal segment (Mtε103-120). Mtε is significantly shorter (61.6 Å) than forms of the subunit in other bacteria, reflecting a shorter C-terminal sequence, proposed to be important in coupling processes via the catalytic β subunit. The C-terminal segment displays an α-helical structure and a highly positive surface charge due to the presence of arginine residues. Using NMR spectroscopy, fluorescence spectroscopy, and mutagenesis, we demonstrate that the new tuberculosis (TB) drug candidate TMC207, proposed to bind to the proton translocating c-ring, also binds to Mtε. A model for the interaction of TMC207 with both ε and the c-ring is presented, suggesting that TMC207 forms a wedge between the two rotating subunits by interacting with the residues W15 and F50 of ε and the c-ring, respectively. T19 and R37 of ε provide the necessary polar interactions with the drug molecule. This new model of the mechanism of TMC207 provides the basis for the design of new drugs targeting the F1F O ATP synthase in M. tuberculosis. Copyright © 2013, American Society for Microbiology. All Rights Reserved.
Source Title: Antimicrobial Agents and Chemotherapy
ISSN: 00664804
DOI: 10.1128/AAC.01039-12
Appears in Collections:Staff Publications

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