Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/102134
Title: Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207
Authors: Rao, Srinivasa P. S.
Biuković, Goran
Basak, Sandip
Manimekalai, Malathy Sony Subramanian
Rishikesan, Sankaranarayanan
Roessle, Manfred
Dick, Thomas
Hunke, Cornelia
Grüber, Gerhard
Keywords: DRNTU::Science::Biological sciences
Issue Date: 2013
Source: Biukovic, G., Basak, S., Manimekalai, M. S. S., Rishikesan, S., Roessle, M., Dick, T., et al. (2013). Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207. Antimicrobial agents and chemotherapy, 57(1), 168-176.
Series/Report no.: Antimicrobial agents and chemotherapy
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) F1FO 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 F1FO ATP synthase in M. tuberculosis.
URI: https://hdl.handle.net/10356/102134
http://hdl.handle.net/10220/16820
ISSN: 0066-4804
DOI: 10.1128/AAC.01039-12
Rights: © 2013, American Society for Microbiology
Fulltext Permission: none
Fulltext Availability: No Fulltext
Appears in Collections:SBS Journal Articles

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