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Variations of subunit Varepsilon of the Mycobacterium tuberculosis F-1Fo ATP Synthase and Novel Model for Mechanism of Action of the Tuberculosis Drug TMC207.

Biukovic, Goran and Basak, Sandip and Manimekalai, Malathy Sony Subramanian and Rishikeshan, Sankaranarayanana and Roessle, Manfred and Dick, Thomas and Rao, Srinivasa and 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 (Mt103-120), 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 Mt103-120 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

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