2LX5

NMR solution structure of peptide epsilon(103-120) from Mycobacterium tuberculosis F-ATPsynthase

Summary for 2LX5

• Entry DOI: 10.2210/pdb2lx5/pdb
• Related: 2RQ6
• NMR Information: BMRB: 18659
• Descriptor: ATP synthase epsilon chain (1 entity in total)
• Functional Keywords: f-atpsynthase, epsilon subunit, alpha helix, coupling subunit, hydrolase inhibitor
• Biological source: Mycobacterium tuberculosis
• Cellular location: Cell membrane; Peripheral membrane protein (By similarity): P63662
• Total number of polymer chains: 1
• Total formula weight: 1924.28

Authors

Basak, S.,Rishikesan, S.,Gruber, G. (deposition date: 2012-08-14, release date: 2012-11-07, Last modification date: 2024-05-15)

Primary citation

Biukovic, G.,Basak, S.,Manimekalai, M.S.,Rishikesan, S.,Roessle, M.,Dick, T.,Rao, S.P.,Hunke, C.,Gruber, G.
Variations of Subunit {varepsilon} of the Mycobacterium tuberculosis F1Fo ATP Synthase and a Novel Model for Mechanism of Action of the Tuberculosis Drug TMC207.
Antimicrob.Agents Chemother., 57:168-176, 2013

PubMed Abstract: The subunit ε of bacterial F(1)F(O) 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) F(1)F(O) ATP synthase and the nuclear magnetic resonance (NMR) structure of its C-terminal segment (Mtε(103-120)). 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 F(1)F(O) ATP synthase in M. tuberculosis.

PubMed: 23089752
DOI: 10.1128/AAC.01039-12

Experimental method

SOLUTION NMR