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dc.contributor.authorWang, Jialiang
dc.contributor.authorLi, Dandan
dc.contributor.authorChen, Lu
dc.contributor.authorCao, Wei
dc.contributor.authorKong, Liangliang
dc.contributor.authorZhang, Wei
dc.contributor.authorCroll, Tristan
dc.contributor.authorDeng, Zixin
dc.contributor.authorLiang, Jingdan
dc.contributor.authorWang, Zhijun
dc.date.accessioned2022-03-06T02:02:20Z
dc.date.available2022-03-06T02:02:20Z
dc.date.issued2022-02-01
dc.identifier.issn2041-1723
dc.identifier.otherPMC8807600
dc.identifier.other35105906
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/334698
dc.description.abstractNonribosomal peptide synthetases (NRPSs) are modular assembly-line megaenzymes that synthesize diverse metabolites with wide-ranging biological activities. The structural dynamics of synthetic elongation has remained unclear. Here, we present cryo-EM structures of PchE, an NRPS elongation module, in distinct conformations. The domain organization reveals a unique "H"-shaped head-to-tail dimeric architecture. The capture of both aryl and peptidyl carrier protein-tethered substrates and intermediates inside the heterocyclization domain and L-cysteinyl adenylate in the adenylation domain illustrates the catalytic and recognition residues. The multilevel structural transitions guided by the adenylation C-terminal subdomain in combination with the inserted epimerase and the conformational changes of the heterocyclization tunnel are controlled by two residues. Moreover, we visualized the direct structural dynamics of the full catalytic cycle from thiolation to epimerization. This study establishes the catalytic trajectory of PchE and sheds light on the rational re-engineering of domain-inserted dimeric NRPSs for the production of novel pharmaceutical agents.
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101528555
dc.sourceessn: 2041-1723
dc.subjectEscherichia coli
dc.subjectRacemases and Epimerases
dc.subjectPeptide Synthases
dc.subjectBacterial Proteins
dc.subjectCryoelectron Microscopy
dc.subjectCatalytic Domain
dc.subjectCatalysis
dc.subjectModels, Molecular
dc.titleCatalytic trajectory of a dimeric nonribosomal peptide synthetase subunit with an inserted epimerase domain.
dc.typeArticle
dc.date.updated2022-03-06T02:02:16Z
prism.issueIdentifier1
prism.publicationNameNat Commun
prism.volume13
dc.identifier.doi10.17863/CAM.82116
dcterms.dateAccepted2022-01-04
rioxxterms.versionofrecord10.1038/s41467-022-28284-x
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidWang, Jialiang [0000-0003-1050-2912]
dc.contributor.orcidLi, Dandan [0000-0003-1394-4097]
dc.contributor.orcidDeng, Zixin [0000-0003-0724-3390]
dc.contributor.orcidLiang, Jingdan [0000-0001-8984-8187]
dc.contributor.orcidWang, Zhijun [0000-0002-9221-2224]
dc.identifier.eissn2041-1723
pubs.funder-project-idWellcome Trust (209407/Z/17/Z)
cam.issuedOnline2022-02


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