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dc.contributor.authorTata, Rolland B
dc.contributor.authorAlsulami, Ali F
dc.contributor.authorSheik Amamuddy, Olivier
dc.contributor.authorBlundell, Tom L
dc.contributor.authorTastan Bishop, Özlem
dc.date.accessioned2022-03-19T02:05:33Z
dc.date.available2022-03-19T02:05:33Z
dc.date.issued2022-01-28
dc.identifier.issn1661-6596
dc.identifier.other35163439
dc.identifier.otherPMC8835989
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/335191
dc.description.abstractThe presence of protein structures with atypical folds in the Protein Data Bank (PDB) is rare and may result from naturally occurring knots or crystallographic errors. Proper characterisation of such folds is imperative to understanding the basis of naturally existing knots and correcting crystallographic errors. If left uncorrected, such errors can frustrate downstream experiments that depend on the structures containing them. An atypical fold has been identified in P. falciparum dihydrofolate reductase (PfDHFR) between residues 20-51 (loop 1) and residues 191-205 (loop 2). This enzyme is key to drug discovery efforts in the parasite, necessitating a thorough characterisation of these folds. Using multiple sequence alignments (MSA), a unique insert was identified in loop 1 that exacerbates the appearance of the atypical fold-giving it a slipknot-like topology. However, PfDHFR has not been deposited in the knotted proteins database, and processing its structure failed to identify any knots within its folds. The application of protein homology modelling and molecular dynamics simulations on the DHFR domain of P. falciparum and those of two other organisms (E. coli and M. tuberculosis) that were used as molecular replacement templates in solving the PfDHFR structure revealed plausible unentangled or open conformations of these loops. These results will serve as guides for crystallographic experiments to provide further insights into the atypical folds identified.
dc.languageeng
dc.publisherMDPI AG
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceessn: 1422-0067
dc.sourcenlmid: 101092791
dc.subjectPdb
dc.subjectAtypical Folds
dc.subjectCrystallographic Error
dc.subjectP. Falciparum Dhfr
dc.subjectSlipknots
dc.subjectPlasmodium falciparum
dc.subjectTetrahydrofolate Dehydrogenase
dc.subjectProtozoan Proteins
dc.subjectCrystallography, X-Ray
dc.subjectSequence Alignment
dc.subjectSequence Analysis, Protein
dc.subjectProtein Conformation
dc.subjectProtein Folding
dc.subjectSequence Homology, Amino Acid
dc.subjectModels, Molecular
dc.subjectDatabases, Protein
dc.subjectMolecular Dynamics Simulation
dc.subjectProtein Domains
dc.titleSlipknot or Crystallographic Error: A Computational Analysis of the Plasmodium falciparum DHFR Structural Folds.
dc.typeArticle
dc.date.updated2022-03-19T02:05:33Z
prism.issueIdentifier3
prism.publicationNameInt J Mol Sci
prism.volume23
dc.identifier.doi10.17863/CAM.82621
dcterms.dateAccepted2022-01-25
rioxxterms.versionofrecord10.3390/ijms23031514
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidTata, Rolland B [0000-0002-8814-5241]
dc.contributor.orcidSheik Amamuddy, Olivier [0000-0002-1781-1382]
dc.contributor.orcidTastan Bishop, Özlem [0000-0001-6861-7849]
dc.identifier.eissn1422-0067
pubs.funder-project-idNIH HHS (U24HG006941)
pubs.funder-project-idWellcome Trust (107740/Z/15/Z)
cam.issuedOnline2022-01-28


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