2lx5
NMR solution structure of peptide epsilon(103-120) from Mycobacterium tuberculosis F-ATPsynthaseNMR solution structure of peptide epsilon(103-120) from Mycobacterium tuberculosis F-ATPsynthase
Structural highlights
FunctionATPE_MYCTU Produces ATP from ADP in the presence of a proton gradient across the membrane. Publication Abstract from PubMedThe subunit epsilon 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 epsilon of Mycobacterium tuberculosis (Mtepsilon) F(1)F(O) ATP synthase and the NMR structure of its C-terminal segment (Mtepsilon(103-120)). The overall length of Mtepsilon (61.6 A) is significantly shorter compared to forms of the subunit in other bacteria, reflecting a shorter C-terminal sequence, proposed to be important in coupling processes via the catalytic beta subunit. The C-terminal segment displays alpha-helical structure and highly positive surface charge due to the presence of arginine residues. Using NMR-, fluorescence spectroscopy and mutagenesis, we demonstrate that the new TB drug candidate TMC207, proposed to bind to the proton translocating c-ring, does also bind to Mtepsilon. A model for the interaction of TMC207 with both, epsilon 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 epsilon and the c-ring, respectively. T19 and R37 of epsilon 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. Variations of subunit {epsilon} of the Mycobacterium tuberculosis F1FO ATP synthase and a novel model for mechanism of action of the TB drug TMC207.,Biukovic G, Basak S, Manimekalai MS, Rishikesan S, Roessle M, Dick T, Rao SP, Hunke C, Gruber G Antimicrob Agents Chemother. 2012 Oct 22. PMID:23089752[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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