A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR

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  • dc.contributor.author Mighell, Taylor L.
  • dc.contributor.author Lehner, Ben, 1978-
  • dc.date.accessioned 2025-10-14T05:37:05Z
  • dc.date.available 2025-10-14T05:37:05Z
  • dc.date.issued 2025
  • dc.description Data de publicació electrònica: 22-09-2025
  • dc.description.abstract Reduced protein abundance is the most frequent mechanism by which rare missense variants cause disease. A promising therapeutic avenue for treating reduced abundance variants is pharmacological chaperones (PCs, also known as correctors or stabilizers), small molecules that bind to and stabilize target proteins. PCs have been approved as clinical treatments for specific variants, but protein energetics suggest their effects might be much more general. To comprehensively assess PC efficacy for variation in a given protein, it is necessary to first assign the molecular mechanism explaining all pathogenic variants, then measure the response to the PC. Here we establish such a framework for the vasopressin 2 receptor (V2R), a G-protein-coupled receptor in which loss-of-function variants cause nephrogenic diabetes insipidus (NDI). Our data show that more than half of NDI variants are poorly expressed, highlighting loss of stability as the major pathogenic mechanism. Treatment with a PC rescues the expression of 87% of destabilized variants. The non-rescued variants identify the drug's predicted binding site. Our results provide proof-of-principle that small molecule binding can rescue destabilizing variants throughout a protein's structure. The application of this principle to other proteins should allow the development of effective therapies for many different rare diseases.
  • dc.description.sponsorship This work was funded by a European Research Council Advanced Grant (883742), Wellcome (220540/Z/20/A), the Spanish Ministry of Science and Innovation (LCF/PR/HR21/52410004, EMBL Partnership, Severo Ochoa Centre of Excellence), the Bettencourt Schueller Foundation, the AXA Research Fund, Agencia de Gestio d’Ajuts Universitaris i de Recerca (AGAUR, 2017 SGR 1322) and the CERCA Program/Generalitat de Catalunya. T.L.M. was funded by an EMBO fellowship (ALTF 113-2021). We thank all members of the Lehner Lab and J. Selent and T. Stepniewski for helpful discussions. We thank the CRG/UPF Flow Cytometry Unit for assistance with the sorting experiments.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Mighell TL, Lehner B. A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR. Nat Struct Mol Biol. 2025 Sep 22. DOI: 10.1038/s41594-025-01659-6
  • dc.identifier.doi http://dx.doi.org/10.1038/s41594-025-01659-6
  • dc.identifier.issn 1545-9993
  • dc.identifier.uri http://hdl.handle.net/10230/71497
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nature structural & molecular biology. 2025 Sep 22
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/883742
  • dc.rights © The Author(s) 2025. 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, 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 Computational biology and bioinformatics
  • dc.subject.keyword Drug discovery
  • dc.subject.keyword Genetics
  • dc.title A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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