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dc.contributor.author | Spagnolli, Giovanni |
dc.contributor.author | Massignan, Tania |
dc.contributor.author | Astolfi, Andrea |
dc.contributor.author | Biggi, Silvia |
dc.contributor.author | Rigoli, Marta |
dc.contributor.author | Brunelli, Paolo |
dc.contributor.author | Libergoli, Michela |
dc.contributor.author | Ianeselli, Alan |
dc.contributor.author | Orioli, Simone |
dc.contributor.author | Boldrini, Alberto |
dc.contributor.author | Terruzzi, Luca |
dc.contributor.author | Bonaldo, Valerio |
dc.contributor.author | Maietta, Giulia |
dc.contributor.author | López Lorenzo, Nuria |
dc.contributor.author | Fernández Flores, Leticia Camila |
dc.contributor.author | Bugallo Codeseira, Yaiza |
dc.contributor.author | Tosatto, Laura |
dc.contributor.author | Linsenmeier, Luise |
dc.contributor.author | Vignoli, Beatrice |
dc.contributor.author | Petris, Gianluca |
dc.contributor.author | Gasparotto, Dino |
dc.contributor.author | Pennuto, Maria |
dc.contributor.author | Guella, Graziano |
dc.contributor.author | Canossa, Marco |
dc.contributor.author | Altmeppen, Hermann C. |
dc.contributor.author | Lolli, Graziano |
dc.contributor.author | Biressi, Stefano |
dc.contributor.author | Martín Pastor, Manuel |
dc.contributor.author | Rodríguez Requena, Jesús |
dc.contributor.author | Mancini, Ines |
dc.contributor.author | Barreca, Maria L. |
dc.contributor.author | Faccioli, Pietro |
dc.contributor.author | Biasini, Emiliano |
dc.date.accessioned | 2021-02-22T11:47:04Z |
dc.date.available | 2021-02-22T11:47:04Z |
dc.date.issued | 2021 |
dc.identifier.citation | Communications Biology volume 4, Article number: 62 (2021) |
dc.identifier.uri | http://hdl.handle.net/10347/24542 |
dc.description.abstract | Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression |
dc.description.sponsorship | L.To. is supported by Fondazione Caritro (Bando Post Doc 2017) and Kennedy’s Disease Association (Research Grant 2018). Research of HCA was supported by the CJD Foundation, Inc. and the Alzheimer Forschung Initiative e.V. (AFI). J.R.R. was funded by a grant (BFU2017-86692-P) from the Spanish Ministry of Economy and Competitiveness, partially funded by FEDER funds. The work was also supported by grants from Fondazione Telethon and Provincia Autonoma di Trento to S.B. (TCP13007), from Fondazione Telethon to E.B. (TCP14009), and by a fellowship from Fondazione Telethon to G.S. S.B. and E.B. are Assistant Telethon Scientists at the Dulbecco Telethon Institute |
dc.language.iso | eng |
dc.publisher | Springer Nature |
dc.rights | © The Author(s) 2021. 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 | Atribución 4.0 Internacional |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ |
dc.subject | Computational biophysics |
dc.subject | Prions |
dc.subject | Virtual screening |
dc.title | Pharmacological inactivation of the prion protein by targeting a folding intermediate |
dc.type | journal article |
dc.identifier.doi | 10.1038/s42003-020-01585-x |
dc.relation.publisherversion | https://doi.org/10.1038/s42003-020-01585-x |
dc.type.hasVersion | VoR |
dc.identifier.essn | 2399-3642 |
dc.rights.accessRights | open access |
dc.contributor.affiliation | Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas |
dc.contributor.affiliation | Universidade de Santiago de Compostela. Departamento de Psiquiatría, Radioloxía, Saúde Pública, Enfermaría e Medicina |
dc.description.peerreviewed | SI |
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© The Author(s) 2021. 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/
© The Author(s) 2021. 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/