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Structure of the ATP synthase from Mycobacterium smegmatis provides targets for treating tuberculosis.

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Montgomery MG, Petri J, Spikes TE, Walker JE
OpenAccess logo Proc Natl Acad Sci U S A 118 (2021)

Cited: 10 times
EuropePMC logo PMID: 34782468

Abstract

The structure has been determined by electron cryomicroscopy of the adenosine triphosphate (ATP) synthase from Mycobacterium smegmatis This analysis confirms features in a prior description of the structure of the enzyme, but it also describes other highly significant attributes not recognized before that are crucial for understanding the mechanism and regulation of the mycobacterial enzyme. First, we resolved not only the three main states in the catalytic cycle described before but also eight substates that portray structural and mechanistic changes occurring during a 360° catalytic cycle. Second, a mechanism of auto-inhibition of ATP hydrolysis involves not only the engagement of the C-terminal region of an α-subunit in a loop in the γ-subunit, as proposed before, but also a "fail-safe" mechanism involving the b'-subunit in the peripheral stalk that enhances engagement. A third unreported characteristic is that the fused bδ-subunit contains a duplicated domain in its N-terminal region where the two copies of the domain participate in similar modes of attachment of the two of three N-terminal regions of the α-subunits. The auto-inhibitory plus the associated "fail-safe" mechanisms and the modes of attachment of the α-subunits provide targets for development of innovative antitubercular drugs. The structure also provides support for an observation made in the bovine ATP synthase that the transmembrane proton-motive force that provides the energy to drive the rotary mechanism is delivered directly and tangentially to the rotor via a Grotthuss water chain in a polar L-shaped tunnel.

Reviews citing this publication (3)

  1. F1·Fo ATP Synthase/ATPase: Contemporary View on Unidirectional Catalysis. Zharova TV, Grivennikova VG, Borisov VB. Int J Mol Sci 24 5417 (2023)
  2. Uncovering interactions between mycobacterial respiratory complexes to target drug-resistant Mycobacterium tuberculosis. McNeil MB, Cheung CY, Waller NJE, Adolph C, Chapman CL, Seeto NEJ, Jowsey W, Li Z, Hameed HMA, Zhang T, Cook GM. Front Cell Infect Microbiol 12 980844 (2022)
  3. Molecular Modeling and Simulation of the Mycobacterial Cell Envelope: From Individual Components to Cell Envelope Assemblies. Brown T, Chavent M, Im W. J Phys Chem B 127 10941-10949 (2023)

Articles citing this publication (7)

  1. Molecular mechanism on forcible ejection of ATPase inhibitory factor 1 from mitochondrial ATP synthase. Kobayashi R, Ueno H, Okazaki KI, Noji H. Nat Commun 14 1682 (2023)
  2. Binding properties of the anti-TB drugs bedaquiline and TBAJ-876 to a mycobacterial F-ATP synthase. Krah A, Grüber G, Bond PJ. Curr Res Struct Biol 4 278-284 (2022)
  3. Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines. Courbon GM, Palme PR, Mann L, Richter A, Imming P, Rubinstein JL. EMBO J 42 e113687 (2023)
  4. Rotary properties of hybrid F1-ATPases consisting of subunits from different species. Watanabe RR, Kiper BT, Zarco-Zavala M, Hara M, Kobayashi R, Ueno H, García-Trejo JJ, Li CB, Noji H. iScience 26 106626 (2023)
  5. Structural Elements Involved in ATP Hydrolysis Inhibition and ATP Synthesis of Tuberculosis and Nontuberculous Mycobacterial F-ATP Synthase Decipher New Targets for Inhibitors. Wong CF, Saw WG, Basak S, Sano M, Ueno H, Kerk HW, Litty D, Ragunathan P, Dick T, Müller V, Noji H, Grüber G. Antimicrob Agents Chemother 66 e0105622 (2022)
  6. Anti-Mycobacterium abscessus Activity of Tuberculosis F-ATP Synthase Inhibitor GaMF1. Ragunathan P, Dick T, Grüber G. Antimicrob Agents Chemother 66 e0001822 (2022)
  7. The Ancestral Shape of the Access Proton Path of Mitochondrial ATP Synthases Revealed by a Split Subunit-a. Wong JE, Zíková A, Gahura O. Mol Biol Evol 40 msad146 (2023)


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