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dc.contributor.authorPrieß, Marten
dc.contributor.authorGöddeke, Hendrik
dc.contributor.authorGroenhof, Gerrit
dc.contributor.authorSchäfer, Lars V.
dc.date.accessioned2018-10-30T10:14:43Z
dc.date.available2018-10-30T10:14:43Z
dc.date.issued2018
dc.identifier.citationPrieß, M., Göddeke, H., Groenhof, G., & Schäfer, L. V. (2018). Molecular Mechanism of ATP Hydrolysis in an ABC Transporter. <i>ACS Central Science</i>, <i>4</i>(10), 1334-1343. <a href="https://doi.org/10.1021/acscentsci.8b00369" target="_blank">https://doi.org/10.1021/acscentsci.8b00369</a>
dc.identifier.otherCONVID_28655610
dc.identifier.otherTUTKAID_79103
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/60020
dc.description.abstractHydrolysis of nucleoside triphosphate (NTP) plays a key role for the function of many biomolecular systems. However, the chemistry of the catalytic reaction in terms of an atomic-level understanding of the structural, dynamic, and free energy changes associated with it often remains unknown. Here, we report the molecular mechanism of adenosine triphosphate (ATP) hydrolysis in the ATP-binding cassette (ABC) transporter BtuCD-F. Free energy profiles obtained from hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations show that the hydrolysis reaction proceeds in a stepwise manner. First, nucleophilic attack of an activated lytic water molecule at the ATP γ-phosphate yields ADP + HPO42- as intermediate product. A conserved glutamate that is located very close to the γ-phosphate transiently accepts a proton and thus acts as catalytic base. In the second step, the proton is transferred back from the catalytic base to the γ-phosphate, yielding ADP + H2PO4-. These two chemical reaction steps are followed by rearrangements of the hydrogen bond network and the coordination of the Mg2+ ion. The rate constant estimated from the computed free energy barriers is in very good agreement with experiments. The overall free energy change of the reaction is close to zero, suggesting that phosphate bond cleavage itself does not provide a power stroke for conformational changes. Instead, ATP binding is essential for tight dimerization of the nucleotide-binding domains and the transition of the transmembrane domains from inward- to outward-facing, whereas ATP hydrolysis resets the conformational cycle. The mechanism is likely relevant for all ABC transporters and might have implications also for other NTPases, as many residues involved in nucleotide binding and hydrolysis are strictly conserved. © 2018 American Chemical Society.en
dc.format.mimetypeapplication/pdf
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.ispartofseriesACS Central Science
dc.rightsIn Copyright
dc.subject.othermolecular mechanism
dc.subject.otherATP hydrolysis
dc.subject.otherABC transporter
dc.titleMolecular Mechanism of ATP Hydrolysis in an ABC Transporter
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201810244518
dc.contributor.laitosKemian laitosfi
dc.contributor.laitosDepartment of Chemistryen
dc.contributor.oppiaineFysikaalinen kemiafi
dc.contributor.oppiainePhysical Chemistryen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.date.updated2018-10-24T12:15:15Z
dc.type.coarhttp://purl.org/coar/resource_type/c_2df8fbb1
dc.description.reviewstatuspeerReviewed
dc.format.pagerange1334-1343
dc.relation.issn2374-7943
dc.relation.numberinseries10
dc.relation.volume4
dc.type.versionpublishedVersion
dc.rights.copyright© 2018 American Chemical Society
dc.rights.accesslevelopenAccessfi
dc.relation.grantnumber304455
dc.subject.ysobiomolekyylit
dc.subject.ysohydrolyysi
dc.subject.ysoadenosiinitrifosfaatti
dc.subject.ysoproteiinit
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p27773
jyx.subject.urihttp://www.yso.fi/onto/yso/p13369
jyx.subject.urihttp://www.yso.fi/onto/yso/p13021
jyx.subject.urihttp://www.yso.fi/onto/yso/p4332
dc.rights.urlhttp://rightsstatements.org/page/InC/1.0/?language=en
dc.relation.doi10.1021/acscentsci.8b00369
dc.relation.funderSuomen Akatemiafi
dc.relation.funderResearch Council of Finlanden
jyx.fundingprogramMuut, SAfi
jyx.fundingprogramOthers, AoFen
jyx.fundinginformationThis work was funded by the Deutsche Forschungsgemeinschaft (DFG) through an Emmy Noether grant to L.V.S. (SCHA 1574/3-1) and Cluster of Excellence RESOLV (EXC 1069). G.G. acknowledges the Academy of Finland for support (Grant 304455).
dc.type.okmA1


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