Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ
Mycobacteria regulate their energy (ATP) levels to sustain their survival even in stringent living conditions. Recent studies have shown that mycobacteria not only slow down their respiratory rate but also block ATP hydrolysis of the F-ATP synthase (α3 :β3 :γ:δ:ε:a:b:b’:c9 ) to maintain ATP hom...
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Main Authors: | , , , , , |
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Other Authors: | |
Format: | Article |
Language: | English |
Published: |
2022
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Subjects: | |
Online Access: | https://hdl.handle.net/10356/155649 |
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Institution: | Nanyang Technological University |
Language: | English |
Summary: | Mycobacteria regulate their energy (ATP) levels to sustain their survival even in stringent
living conditions. Recent studies have shown that mycobacteria not only slow down their respiratory
rate but also block ATP hydrolysis of the F-ATP synthase (α3
:β3
:γ:δ:ε:a:b:b’:c9
) to maintain ATP homeostasis in situations not amenable for growth. The mycobacteria-specific α C-terminus (α533-545)
has unraveled to be the major regulative of latent ATP hydrolysis. Its deletion stimulates ATPase
activity while reducing ATP synthesis. In one of the six rotational states of F-ATP synthase, α533-545
has been visualized to dock deep into subunit γ, thereby blocking rotation of γ within the engine.
The functional role(s) of this C-terminus in the other rotational states are not clarified yet and are
being still pursued in structural studies. Based on the interaction pattern of the docked α533-545
region with subunit γ, we attempted to study the druggability of the α533-545 motif. In this direction, our computational work has led to the development of an eight-featured α533-545 peptide
pharmacophore, followed by database screening, molecular docking, and pose selection, resulting in
eleven hit molecules. ATP synthesis inhibition assays using recombinant ATP synthase as well as mycobacterial inverted membrane vesicles show that one of the hits, AlMF1, inhibited the mycobacterial
F-ATP synthase in a micromolar range. The successful targeting of the α533-545-γ interaction motif
demonstrates the potential to develop inhibitors targeting the α site to interrupt rotary coupling with
ATP synthesis. |
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