Variations of subunit Varepsilon of the Mycobacterium tuberculosis F-1Fo ATP Synthase and Novel Model for Mechanism of Action of the Tuberculosis Drug TMC207.
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Biukovic, Goran, Basak, Sandip, Manimekalai, Malathy Sony Subramanian, Rishikeshan, Sankaranarayanana, Roessle, Manfred, Dick, Thomas, Rao, Srinivasa, Hunke, Cornelia and Gruber, Gerhard (2013) Variations of subunit Varepsilon of the Mycobacterium tuberculosis F-1Fo ATP Synthase and Novel Model for Mechanism of Action of the Tuberculosis Drug TMC207. Antimicrobial Agents and Chemotherapy, 57 (1). pp. 168-176. ISSN 0066-4804
Abstract
Subunit ε of bacterial F-ATP synthases plays an important role in regulation by affecting the coupling, catalytic pathway, and inhibition of ATP hydrolysis, achieved through conformational transitions of its C-terminal domain. Here we present the low resolution solution structure of ε of Mycobacterium tuberculosis (Mtε) F-ATP synthase and the NMR structure of its C-terminal segment (Mt103-120), displaying an α-helical region between residues 104-119. The overall length of Mtε (61.6 Å) is significantly shorter compared to other bacterial forms, reflected by the missing C-terminal segment, described to be important in coupling processes via the catalytic β subunit. The surface potential of Mt103-120 reveals highly positive surface charge due to the presence of arginine residues. The unique structural traits of the C-terminus of Mtε make this segment a promising epitope for compounds to bind.
Using NMR- and fluorescence spectroscopy, we demonstrate that the TB drug TMC207, proposed to bind to the proton translocating c-ring, does also bind to Mtε. W15 has been identified as one of the interacting residues. A model for the interaction of TMC207 with both the ε and the c-ring is presented, showing 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. The other two residues, T19 and R37 of ε give the necessary polar interaction to the drug molecule. The new mechanism of TMC207 binding opens a promising platform for the design of antimycobacterials that effictively inhibit the ATP synthase in M. tuberculosis.
| Item Type: | Article |
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| Keywords: | ATP epsilon; Tuberculosis |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/6571 |