In:
The FEBS Journal, Wiley, Vol. 289, No. 20 ( 2022-10), p. 6308-6323
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 1 F O 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 O sector and ATP formation in the F 1 headpiece of the bipartite F 1 F O 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 ( Mab ε), 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 Mab ε 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 Mab ε's lack of ATP binding. Based on the structural insights, we conducted an in silico inhibitor screen. One hit, Ep1 Mab F1, was shown to inhibit the growth of Mab and bacterial ATP synthesis. NMR titration experiments and docking studies described the binding epitopes of Ep1 Mab F1 on Mab ε. Together, our data demonstrate the potential to develop inhibitors targeting the ε subunit of Mab F 1 F O ATP synthase to interrupt the coupling process.
Type of Medium:
Online Resource
ISSN:
1742-464X
,
1742-4658
DOI:
10.1111/febs.v289.20
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2172518-4
SSG:
12
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