2LX5

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

2LX5 の概要

• エントリーDOI: 10.2210/pdb2lx5/pdb
• 関連するPDBエントリー: 2RQ6
• NMR情報: BMRB: 18659
• 分子名称: ATP synthase epsilon chain (1 entity in total)
• 機能のキーワード: f-atpsynthase, epsilon subunit, alpha helix, coupling subunit, hydrolase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• 細胞内の位置: Cell membrane; Peripheral membrane protein (By similarity): P63662
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 1924.28

構造登録者

Basak, S.,Rishikesan, S.,Gruber, G. (登録日: 2012-08-14, 公開日: 2012-11-07, 最終更新日: 2024-05-15)

主引用文献

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

実験手法

SOLUTION NMR