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dc.contributor.authorHarris, Andrzej
dc.contributor.authorWagner, Manuel
dc.contributor.authorDu, Dijun
dc.contributor.authorRaschka, Stefanie
dc.contributor.authorNentwig, Lea-Marie
dc.contributor.authorGohlke, Holger
dc.contributor.authorSmits, Sander HJ
dc.contributor.authorLuisi, Ben
dc.contributor.authorSchmitt, Lutz
dc.date.accessioned2021-11-06T00:31:34Z
dc.date.available2021-11-06T00:31:34Z
dc.date.issued2021-09-06
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330379
dc.description.abstractPdr5, a member of the extensive ABC transporter superfamily, is representative of a clinically relevant subgroup involved in pleiotropic drug resistance. Pdr5 and its homologues drive drug efflux through uncoupled hydrolysis of nucleotides, enabling organisms such as baker's yeast and pathogenic fungi to survive in the presence of chemically diverse antifungal agents. Here, we present the molecular structure of Pdr5 solved with single particle cryo-EM, revealing details of an ATP-driven conformational cycle, which mechanically drives drug translocation through an amphipathic channel, and a clamping switch within a conserved linker loop that acts as a nucleotide sensor. One half of the transporter remains nearly invariant throughout the cycle, while its partner undergoes changes that are transmitted across inter-domain interfaces to support a peristaltic motion of the pumped molecule. The efflux model proposed here rationalises the pleiotropic impact of Pdr5 and opens new avenues for the development of effective antifungal compounds.
dc.description.sponsorshipOpen Access funding enabled and organized by Projekt DEAL.
dc.languageeng
dc.publisherNature Research
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectATP-Binding Cassette Transporters
dc.subjectAdenosine Triphosphate
dc.subjectCatalytic Domain
dc.subjectCryoelectron Microscopy
dc.subjectDetergents
dc.subjectDrug Resistance, Fungal
dc.subjectGenetic Pleiotropy
dc.subjectHydrolysis
dc.subjectMutation
dc.subjectProtein Conformation
dc.subjectProtein Domains
dc.subjectRhodamines
dc.subjectSaccharomyces cerevisiae Proteins
dc.subjectVanadates
dc.titleStructure and efflux mechanism of the yeast pleiotropic drug resistance transporter Pdr5.
dc.typeArticle
prism.endingPage5254
prism.issueIdentifier1
prism.publicationNameNature Communications
prism.startingPage5254
prism.volume12
dc.identifier.doi10.17863/CAM.77822
dcterms.dateAccepted2021-08-11
rioxxterms.versionofrecord10.1038/s41467-021-25574-8
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-08-11
dc.contributor.orcidLuisi, Ben [0000-0003-1144-9877]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEuropean Research Council (742210)
pubs.funder-project-idWellcome Trust (200873/Z/16/Z)
cam.issuedOnline2021-09-06


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