Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/163128
Title: Structural elements involved in ATP hydrolysis inhibition and ATP synthesis of tuberculosis and non-tuberculous mycobacterial F-ATP synthase decipher new targets for inhibitors
Authors: Wong, Chui Fann
Saw, Wuan Geok
Basak, Sandip
Sano, Mio
Ueno, Hiroshi
Kerk, Hwee Wen
Litty, Dennis
Ragunathan, Priya
Dick, Thomas
Müller, Volker
Noji, Hiroyuki
Grüber, Gerhard
Keywords: Science::Biological sciences::Biochemistry
Issue Date: 2022
Source: Wong, C. F., Saw, W. G., Basak, S., Sano, M., Ueno, H., Kerk, H. W., Litty, D., Ragunathan, P., Dick, T., Müller, V., Noji, H. & Grüber, G. (2022). Structural elements involved in ATP hydrolysis inhibition and ATP synthesis of tuberculosis and non-tuberculous mycobacterial F-ATP synthase decipher new targets for inhibitors. Antimicrobial Agents and Chemotherapy. https://dx.doi.org/10.1128/aac.01056-22
Project: NRF-CRP18-2017-01
Journal: Antimicrobial Agents and Chemotherapy 
Abstract: The F1FO-ATP synthase is required for the viability of tuberculosis- (TB) and non- tuberculous mycobacteria (NTM) and has been validated as a drug-target. Here, we present the cryo-EM structures of the Mycobacterium smegmatis F1-ATPase and the F1FO-ATP synthase with different nucleotide occupation within the catalytic sites and visualize critical elements for latent ATP hydrolysis and efficient ATP synthesis. Mutational studies reveal that the extended C-terminal domain (αCTD) of subunit α is the main element for the self-inhibition mechanism of ATP hydrolysis for TB and NTM bacteria. Rotational studies indicate that the transition between the inhibition state by the ɑCTD and the active state is a rapid process. We 40 demonstrate that the unique mycobacterial γ-loop and subunit δ are critical elements required for ATP formation. The data underline that these mycobacterium specific elements of α, γ and δ are attractive targets, providing a platform for the discovery of species-specific inhibitors.
URI: https://hdl.handle.net/10356/163128
ISSN: 0066-4804
DOI: 10.1128/aac.01056-22
Rights: © 2022 American Society for Microbiology. All Rights Reserved. This paper was published in Antimicrobial Agents and Chemotherapy and is made available with permission of American Society for Microbiology.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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