Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207
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 m...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2013
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| Online Access: | https://hdl.handle.net/10356/102134 http://hdl.handle.net/10220/16820 |
| _version_ | 1826127198312988672 |
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| author | Rao, Srinivasa P. S. Biuković, Goran Basak, Sandip Manimekalai, Malathy Sony Subramanian Rishikesan, Sankaranarayanan Roessle, Manfred Dick, Thomas Hunke, Cornelia Grüber, Gerhard |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Rao, Srinivasa P. S. Biuković, Goran Basak, Sandip Manimekalai, Malathy Sony Subramanian Rishikesan, Sankaranarayanan Roessle, Manfred Dick, Thomas Hunke, Cornelia Grüber, Gerhard |
| author_sort | Rao, Srinivasa P. S. |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T07:04:52Z |
| format | Journal Article |
| id | ntu-10356/102134 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:04:52Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | ntu-10356/1021342022-02-16T16:28:09Z Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207 Rao, Srinivasa P. S. Biuković, Goran Basak, Sandip Manimekalai, Malathy Sony Subramanian Rishikesan, Sankaranarayanan Roessle, Manfred Dick, Thomas Hunke, Cornelia Grüber, Gerhard School of Biological Sciences DRNTU::Science::Biological sciences 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. 2013-10-24T08:08:09Z 2019-12-06T20:50:11Z 2013-10-24T08:08:09Z 2019-12-06T20:50:11Z 2013 2013 Journal Article 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. 0066-4804 https://hdl.handle.net/10356/102134 http://hdl.handle.net/10220/16820 10.1128/AAC.01039-12 23089752 en Antimicrobial agents and chemotherapy © 2013, American Society for Microbiology |
| spellingShingle | DRNTU::Science::Biological sciences Rao, Srinivasa P. S. Biuković, Goran Basak, Sandip Manimekalai, Malathy Sony Subramanian Rishikesan, Sankaranarayanan Roessle, Manfred Dick, Thomas Hunke, Cornelia Grüber, Gerhard Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207 |
| 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 |
| title_full | Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207 |
| title_fullStr | Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207 |
| title_full_unstemmed | Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207 |
| title_short | Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207 |
| title_sort | variations of subunit ε of the mycobacterium tuberculosis f1fo atp synthase and a novel model for mechanism of action of the tuberculosis drug tmc207 |
| topic | DRNTU::Science::Biological sciences |
| url | https://hdl.handle.net/10356/102134 http://hdl.handle.net/10220/16820 |
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