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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sg-ntu-dr.10356-1556492023-02-28T17:09:31Z Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ Harikishore, Amaravadhi Wong, Chui-Fann Ragunathan, Priya Litty, Dennis Müller, Volker Grüber, Gerhard School of Biological Sciences Science::Biological sciences::Biochemistry Tuberculosis Mycobacteria F-ATP synthase Bioenergetics Inhibitor Pharmacophore 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. National Research Foundation (NRF) Published version This research was supported by the National Research Foundation (NRF) Singapore, Competitive Research Programme (CRP), Grant Award Number NRF-CRP18-2017-01, and the Deutsche Forschungsgemeinschaft via SFB807. 2022-03-11T07:16:58Z 2022-03-11T07:16:58Z 2021 Journal Article Harikishore, A., Wong, C., Ragunathan, P., Litty, D., Müller, V. & Grüber, G. (2021). Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ. Antibiotics, 10(12), 1456-1465. https://dx.doi.org/10.3390/antibiotics10121456 2079-6382 https://hdl.handle.net/10356/155649 10.3390/antibiotics10121456 12 10 1456 1465 en NRF-CRP18-2017-01 Antibiotics © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). application/pdf |
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Science::Biological sciences::Biochemistry Tuberculosis Mycobacteria F-ATP synthase Bioenergetics Inhibitor Pharmacophore Harikishore, Amaravadhi Wong, Chui-Fann Ragunathan, Priya Litty, Dennis Müller, Volker Grüber, Gerhard Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ |
description |
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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School of Biological Sciences |
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School of Biological Sciences Harikishore, Amaravadhi Wong, Chui-Fann Ragunathan, Priya Litty, Dennis Müller, Volker Grüber, Gerhard |
format |
Article |
author |
Harikishore, Amaravadhi Wong, Chui-Fann Ragunathan, Priya Litty, Dennis Müller, Volker Grüber, Gerhard |
author_sort |
Harikishore, Amaravadhi |
title |
Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ |
title_short |
Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ |
title_full |
Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ |
title_fullStr |
Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ |
title_full_unstemmed |
Targeting mycobacterial F-ATP synthase C-terminal α subunit interaction motif on rotary subunit γ |
title_sort |
targeting mycobacterial f-atp synthase c-terminal α subunit interaction motif on rotary subunit γ |
publishDate |
2022 |
url |
https://hdl.handle.net/10356/155649 |
_version_ |
1759853120064585728 |