7XKZ

Solution structure of subunit epsilon of the Mycobacterium abscessus F-ATP synthase

Summary for 7XKZ

• Entry DOI: 10.2210/pdb7xkz/pdb
• Descriptor: ATP synthase epsilon chain (1 entity in total)
• Functional Keywords: mycobacteria, f-atp synthase, bioenergetics, oxidative phosphorylation, electron transport
• Biological source: Mycobacteroides abscessus
• Total number of polymer chains: 1
• Total formula weight: 13903.49

Authors

Shin, J.,Grueber, G.,Harikishore, A.,Wong, C.F.,Prya, R.,Dick, T. (deposition date: 2022-04-20, release date: 2023-03-08, Last modification date: 2024-05-15)

Primary citation

Shin, J.,Harikishore, A.,Wong, C.F.,Ragunathan, P.,Dick, T.,Gruber, G.
Atomic solution structure of Mycobacterium abscessus F-ATP synthase subunit epsilon and identification of Ep1MabF1 as a targeted inhibitor.
Febs J., 289:6308-6323, 2022

PubMed Abstract: Mycobacterium abscessus (Mab) is a nontuberculous mycobacterium of increasing clinical relevance. The rapidly growing opportunistic pathogen is intrinsically multi-drug-resistant and causes difficult-to-cure lung disease. Adenosine triphosphate, generated by the essential F F ATP synthase, is the major energy currency of the pathogen, bringing this enzyme complex into focus for the discovery of novel antimycobacterial compounds. Coupling of proton translocation through the membrane-embedded F sector and ATP formation in the F headpiece of the bipartite F F ATP synthase occurs via the central stalk subunits γ and ε. Here, we used solution NMR spectroscopy to resolve the first atomic structure of the Mab subunit ε (Mabε), showing that it consists of an N-terminal β-barrel domain (NTD) and a helix-loop-helix motif in its C-terminal domain (CTD). NMR relaxation measurements of Mabε shed light on dynamic epitopes and amino acids relevant for coupling processes within the protein. We describe structural differences between other mycobacterial ε subunits and Mabε's lack of ATP binding. Based on the structural insights, we conducted an in silico inhibitor screen. One hit, Ep1MabF1, was shown to inhibit the growth of Mab and bacterial ATP synthesis. NMR titration experiments and docking studies described the binding epitopes of Ep1MabF1 on Mabε. Together, our data demonstrate the potential to develop inhibitors targeting the ε subunit of Mab F F ATP synthase to interrupt the coupling process.

PubMed: 35612822
DOI: 10.1111/febs.16536

Experimental method

SOLUTION NMR