A glutamine-based single α-helix scaffold to target globular proteins

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• dc.contributor.author Escobedo, Albert
• dc.contributor.author Piccirillo, Jonathan
• dc.contributor.author Aranda, Juan
• dc.contributor.author Diercks, Tammo
• dc.contributor.author Mateos, Borja
• dc.contributor.author Garcia-Cabau, Carla
• dc.contributor.author Sánchez-Navarro, Macarena
• dc.contributor.author Topal, Busra
• dc.contributor.author Biesaga, Mateusz
• dc.contributor.author Staby, Lasse
• dc.contributor.author Kragelund, Birthe B.
• dc.contributor.author García, Jesús
• dc.contributor.author Millet, Oscar
• dc.contributor.author Orozco, Modesto
• dc.contributor.author Coles, Murray
• dc.contributor.author Crehuet, Ramon
• dc.contributor.author Salvatella, Xavier
• dc.date.accessioned 2023-01-24T07:19:36Z
• dc.date.available 2023-01-24T07:19:36Z
• dc.date.issued 2022
• dc.description.abstract The binding of intrinsically disordered proteins to globular ones can require the folding of motifs into α-helices. These interactions offer opportunities for therapeutic intervention but their modulation with small molecules is challenging because they bury large surfaces. Linear peptides that display the residues that are key for binding can be targeted to globular proteins when they form stable helices, which in most cases requires their chemical modification. Here we present rules to design peptides that fold into single α-helices by instead concatenating glutamine side chain to main chain hydrogen bonds recently discovered in polyglutamine helices. The resulting peptides are uncharged, contain only natural amino acids, and their sequences can be optimized to interact with specific targets. Our results provide design rules to obtain single α-helices for a wide range of applications in protein engineering and drug design.
• dc.description.sponsorship We thank Luis Serrano for help with the Agadir predictions and helpful discussions, Ben Lehner and Ernest Giralt for helpful discussions and the ICTS NMR facility, managed by the scientific and technological centers of the University of Barcelona (CCiT UB), for their help in NMR. B.M. acknowledges funding from the Asociación Española contra el Cáncer (FCAECC project #POSTD211371MATE). C.G. acknowledges a graduate fellowship from MINECO (PRE2018-084684). M.S.-N. acknowledges funding from MINECO (PID2020-119810RB-I00). M.S.-N. holds a Ramón y Cajal contract (RYC2018-024759-I) from the Spanish Ministry of Science, Innovation, and Universities. X.S. acknowledges funding from AGAUR (2017 SGR 324), MINECO (BIO2015-70092-R and PID2019-110198RB-I00), and the European Research Council (CONCERT, contract number 648201). B.B.K acknowledges funding from the Novo Nordisk Foundation (#NNF18OC0033926). M.O. acknowledges funding from the Instituto Nacional de Bioinformática, The EU BioExcel Centre of Excellence for HPC and the Spanish Ministry of Science (PID2021-122478NB-I00) and the Instituto de Salud Carlos III–Instituto Nacional de Bioinformatica (ISCIII PT 17/0009/0007 co-funded by the Fondo Europeo de Desarrollo Regional). M.O. is an ICREA Academy scholar and J.A. is a Juan de la Cierva fellow. M.C. was supported by institutional funds of the Max Planck Society. This project has been carried out using the resources of CSUC. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain).
• dc.format.mimetype application/pdf
• dc.identifier.citation Escobedo A, Piccirillo J, Aranda J, Diercks T, Mateos B, Garcia-Cabau C, Sánchez-Navarro M, Topal B, Biesaga M, Staby L, Kragelund BB, García J, Millet O, Orozco M, Coles M, Crehuet R, Salvatella X. A glutamine-based single α-helix scaffold to target globular proteins. Nat Commun. 2022 Nov 18;13(1):7073. DOI: 10.1038/s41467-022-34793-6
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-022-34793-6
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/55410
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2022 Nov 18;13(1):7073
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/648201
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PRE2018-084684
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119810RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2015-70092-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-110198RB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-122478NB-I00
• dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Biophysical chemistry
• dc.subject.keyword Intrinsically disordered proteins
• dc.subject.keyword Peptides
• dc.subject.keyword Solution-state NMR
• dc.title A glutamine-based single α-helix scaffold to target globular proteins
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion