dc.contributor.authorBiuković, Goran
dc.contributor.authorBasak, Sandip
dc.contributor.authorManimekalai, Malathy Sony Subramanian
dc.contributor.authorRishikesan, Sankaranarayanan
dc.contributor.authorRoessle, Manfred
dc.contributor.authorDick, Thomas
dc.contributor.authorRao, Srinivasa P. S.
dc.contributor.authorHunke, Cornelia
dc.contributor.authorGrüber, Gerhard
dc.date.accessioned2013-10-24T08:08:09Z
dc.date.available2013-10-24T08:08:09Z
dc.date.copyright2013en_US
dc.date.issued2013
dc.identifier.citationBiukovic, 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.en_US
dc.identifier.issn0066-4804en_US
dc.identifier.urihttp://hdl.handle.net/10220/16820
dc.description.abstractThe 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.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesAntimicrobial agents and chemotherapyen_US
dc.rights© 2013, American Society for Microbiologyen_US
dc.subjectDRNTU::Science::Biological sciences
dc.titleVariations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207en_US
dc.typeJournal Article
dc.contributor.schoolSchool of Biological Sciencesen_US
dc.identifier.doihttp://dx.doi.org/10.1128/AAC.01039-12


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