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dc.contributor.authorMorris, EPen_US
dc.contributor.authorda Fonseca, PCAen_US
dc.date.accessioned2017-11-22T11:42:48Z
dc.date.issued2017-06en_US
dc.identifier.citationActa crystallographica. Section D, Structural biology, 2017, 73 (Pt 6), pp. 522 - 533en_US
dc.identifier.issn2059-7983en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/925
dc.identifier.eissn2059-7983en_US
dc.identifier.doi10.1107/s2059798317007021en_US
dc.description.abstractWith the recent advances in biological structural electron microscopy (EM), protein structures can now be obtained by cryo-EM and single-particle analysis at resolutions that used to be achievable only by crystallographic or NMR methods. We have explored their application to study protein-ligand interactions using the human 20S proteasome, a well established target for cancer therapy that is also being investigated as a target for an increasing range of other medical conditions. The map of a ligand-bound human 20S proteasome served as a proof of principle that cryo-EM is emerging as a realistic approach for more general structural studies of protein-ligand interactions, with the potential benefits of extending such studies to complexes that are unfavourable to other methods and allowing structure determination under conditions that are closer to physiological, preserving ligand specificity towards closely related binding sites. Subsequently, the cryo-EM structure of the Plasmodium falciparum 20S proteasome, with a new prototype specific inhibitor bound, revealed the molecular basis for the ligand specificity towards the parasite complex, which provides a framework to guide the development of highly needed new-generation antimalarials. Here, the cryo-EM analysis of the ligand-bound human and P. falciparum 20S proteasomes is reviewed, and a complete description of the methods used for structure determination is provided, including the strategy to overcome the bias orientation of the human 20S proteasome on electron-microscope grids and details of the icr3d software used for three-dimensional reconstruction.en_US
dc.formatPrint-Electronicen_US
dc.format.extent522 - 533en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectHumansen_US
dc.subjectPlasmodium falciparumen_US
dc.subjectMalaria, Falciparumen_US
dc.subjectProteasome Endopeptidase Complexen_US
dc.subjectAntimalarialsen_US
dc.subjectCryoelectron Microscopyen_US
dc.subjectCrystallography, X-Rayen_US
dc.subjectDrug Designen_US
dc.subjectProteasome Inhibitorsen_US
dc.titleHigh-resolution cryo-EM proteasome structures in drug development.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-05-10en_US
rioxxterms.versionofrecord10.1107/s2059798317007021en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2017-06en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfActa crystallographica. Section D, Structural biologyen_US
pubs.issuePt 6en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Structural Biology/Structural Electron Microscopy
pubs.publication-statusPublisheden_US
pubs.volume73en_US
pubs.embargo.termsNot knownen_US
icr.researchteamStructural Electron Microscopyen_US
dc.contributor.icrauthorMorris, Edwarden_US


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