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dc.contributor.authorMontgomery, Martin G
dc.contributor.authorPetri, Jessica
dc.contributor.authorSpikes, Tobias E
dc.contributor.authorWalker, John
dc.date.accessioned2022-01-07T16:50:04Z
dc.date.available2022-01-07T16:50:04Z
dc.date.issued2021-11-23
dc.identifier.issn0027-8424
dc.identifier.otherPMC8617483
dc.identifier.other34782468
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/332375
dc.description.abstractThe 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.
dc.languageeng
dc.publisherProceedings of the National Academy of Sciences
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1091-6490
dc.sourcenlmid: 7505876
dc.subjectStructure
dc.subjectRegulation
dc.subjectMycobacteria
dc.subjectATP synthase
dc.subjectRotary Mechanism
dc.subjectAnimals
dc.subjectCattle
dc.subjectMycobacterium smegmatis
dc.subjectTuberculosis
dc.subjectMitochondrial Proton-Translocating ATPases
dc.subjectProteins
dc.subjectBacterial Proteins
dc.subjectProtein Subunits
dc.subjectAdenosine Triphosphate
dc.subjectAntitubercular Agents
dc.subjectCryoelectron Microscopy
dc.subjectProtein Conformation
dc.subjectProton-Motive Force
dc.subjectHydrolysis
dc.subjectModels, Molecular
dc.titleStructure of the ATP synthase from Mycobacterium smegmatis provides targets for treating tuberculosis.
dc.typeArticle
dc.date.updated2022-01-07T16:50:03Z
prism.issueIdentifier47
prism.publicationNameProc Natl Acad Sci U S A
prism.volume118
dc.identifier.doi10.17863/CAM.79821
dcterms.dateAccepted2021-10-13
rioxxterms.versionofrecord10.1073/pnas.2111899118
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidMontgomery, Martin G [0000-0001-6142-9423]
dc.contributor.orcidSpikes, Tobias E [0000-0002-2432-8006]
dc.contributor.orcidWalker, John [0000-0001-7929-2162]
dc.identifier.eissn1091-6490
pubs.funder-project-idMedical Research Council (MC_EX_MR/M009858/1)
pubs.funder-project-idMRC (MC_UU_00015/8)
cam.issuedOnline2021-11-15


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International