Determining protein structures using deep mutagenesis

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• dc.contributor.author Schmiedel, Jörn M.
• dc.contributor.author Lehner, Ben, 1978-
• dc.date.accessioned 2019-06-20T06:37:32Z
• dc.date.issued 2019
• dc.description.abstract Determining the three-dimensional structures of macromolecules is a major goal of biological research, because of the close relationship between structure and function; however, thousands of protein domains still have unknown structures. Structure determination usually relies on physical techniques including X-ray crystallography, NMR spectroscopy and cryo-electron microscopy. Here we present a method that allows the high-resolution three-dimensional backbone structure of a biological macromolecule to be determined only from measurements of the activity of mutant variants of the molecule. This genetic approach to structure determination relies on the quantification of genetic interactions (epistasis) between mutations and the discrimination of direct from indirect interactions. This provides an alternative experimental strategy for structure determination, with the potential to reveal functional and in vivo structures.
• dc.description.sponsorship This work was supported by a European Research Council (ERC) Consolidator grant (616434), the Spanish Ministry of Economy, Industry and Competitiveness (MEIC; BFU2017-89488-P), the AXA Research Fund, the Bettencourt Schueller Foundation, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322), the EMBL-CRG Systems Biology Program and the CERCA Program/Generalitat de Catalunya. J.M.S. was supported by an EMBO Long-Term Fellowship (ALTF 857-2016). This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 752809 (J.M.S.). We acknowledge support from the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership and the Centro de Excelencia Severo Ochoa.
• dc.format.mimetype application/pdf
• dc.identifier.citation Schmiedel JM, Lehner B. Determining protein structures using deep mutagenesis. Nat Genet. 2019; 51(7):1177-1186. DOI 10.1038/s41588-019-0431-x
• dc.identifier.doi http://dx.doi.org/10.1038/s41588-019-0431-x
• dc.identifier.issn 1061-4036
• dc.identifier.uri http://hdl.handle.net/10230/41849
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Genet. 2019; 51(7):1177-1186
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/616434
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/752809
• dc.rights © Springer Nature Publishing AG Schmiedel JM, Lehner B. Determining protein structures using deep mutagenesis. Nat Genet. 2019. DOI 10.1038/s41588-019-0431-x [http://dx.doi.org/10.1038/s41588-019-0431-x]
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Computational biology and bioinformatics
• dc.subject.keyword Genetics
• dc.subject.keyword High-throughput screening
• dc.subject.keyword Structural biology
• dc.title Determining protein structures using deep mutagenesis
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion