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Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207

หน่วยงาน Nanyang Technological University, Singapore

รายละเอียด

ชื่อเรื่อง : Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207
นักวิจัย : Biuković, Goran , Basak, Sandip , Manimekalai, Malathy Sony Subramanian , Rishikesan, Sankaranarayanan , Roessle, Manfred , Dick, Thomas , Rao, Srinivasa P. S. , Hunke, Cornelia , Grüber, Gerhard
คำค้น : DRNTU::Science::Biological sciences
หน่วยงาน : Nanyang Technological University, Singapore
ผู้ร่วมงาน : -
ปีพิมพ์ : 2556
อ้างอิง : 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 , http://hdl.handle.net/10220/16820 , http://dx.doi.org/10.1128/AAC.01039-12
ที่มา : -
ความเชี่ยวชาญ : -
ความสัมพันธ์ : Antimicrobial agents and chemotherapy
ขอบเขตของเนื้อหา : -
บทคัดย่อ/คำอธิบาย :

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.

บรรณานุกรม :
Biuković, Goran , Basak, Sandip , Manimekalai, Malathy Sony Subramanian , Rishikesan, Sankaranarayanan , Roessle, Manfred , Dick, Thomas , Rao, Srinivasa P. S. , Hunke, Cornelia , Grüber, Gerhard . (2556). Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207.
    กรุงเทพมหานคร : Nanyang Technological University, Singapore.
Biuković, Goran , Basak, Sandip , Manimekalai, Malathy Sony Subramanian , Rishikesan, Sankaranarayanan , Roessle, Manfred , Dick, Thomas , Rao, Srinivasa P. S. , Hunke, Cornelia , Grüber, Gerhard . 2556. "Variations of subunit ε of the mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207".
    กรุงเทพมหานคร : Nanyang Technological University, Singapore.
Biuković, Goran , Basak, Sandip , Manimekalai, Malathy Sony Subramanian , Rishikesan, Sankaranarayanan , Roessle, Manfred , Dick, Thomas , Rao, Srinivasa P. S. , 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."
    กรุงเทพมหานคร : Nanyang Technological University, Singapore, 2556. Print.
Biuković, Goran , Basak, Sandip , Manimekalai, Malathy Sony Subramanian , Rishikesan, Sankaranarayanan , Roessle, Manfred , Dick, Thomas , Rao, Srinivasa P. S. , 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. กรุงเทพมหานคร : Nanyang Technological University, Singapore; 2556.