Selective targeting of ligand-dependent and -independent signaling by GPCR conformation-specific anti-US28 intrabodies
| Autor: | Nick D. Bergkamp, Martine J. Smit, Truc Giap, Connie R. Jimenez, K. Christopher Garcia, Hidde L. Ploegh, Timo W.M. De Groof, Maarten P. Bebelman, Richard de Goeij de Haas, Raimond Heukers, Sander R. Piersma, Marco Siderius |
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| Přispěvatelé: | Medicinal chemistry, AIMMS, Pathology, Medical oncology laboratory, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Neurodegeneration, Supporting clinical sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Science Tumor spheroid Molecular Conformation General Physics and Astronomy Cytomegalovirus Plasma protein binding Ligands General Biochemistry Genetics and Molecular Biology Intrabody Article Receptors G-Protein-Coupled 03 medical and health sciences Viral Proteins 0302 clinical medicine Receptor pharmacology Tandem Mass Spectrometry Spheroids Cellular Antibody fragment therapy Humans Receptor beta-Arrestins G protein-coupled receptor Multidisciplinary biology Chemistry Ligand Chemokine CX3CL1 HEK 293 cells General Chemistry Single-Domain Antibodies Cell biology 030104 developmental biology HEK293 Cells Gq alpha subunit 030220 oncology & carcinogenesis biology.protein Receptors Chemokine Chromatography Liquid Protein Binding Signal Transduction |
| Zdroj: | Nature Communications Nature Communications, 12(1):4357. Nature Publishing Group De Groof, T W M, Bergkamp, N D, Heukers, R, Giap, T, Bebelman, M P, Goeij-de Haas, R, Piersma, S R, Jimenez, C R, Garcia, K C, Ploegh, H L, Siderius, M & Smit, M J 2021, ' Selective targeting of ligand-dependent and-independent signaling by GPCR conformation-specific anti-US28 intrabodies ', Nature Communications, vol. 12, no. 1, pp. 4357 . https://doi.org/10.1038/s41467-021-24574-y Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021) Nature Communications, 12(1). Nature Publishing Group UK De Groof, T W M, Bergkamp, N D, Heukers, R, Giap, T, Bebelman, M P, Goeij-de Haas, R, Piersma, S R, Jimenez, C R, Garcia, K C, Ploegh, H L, Siderius, M & Smit, M J 2021, ' Selective targeting of ligand-dependent and-independent signaling by GPCR conformation-specific anti-US28 intrabodies ', Nature Communications, vol. 12, no. 1, 4357 . https://doi.org/10.1038/s41467-021-24574-y |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-24574-y |
| Popis: | While various GPCRs, including US28, display constitutive, ligand-independent activity, it remains to be established whether ligand-dependent and -independent active conformations differ and can be selectively modulated. Previously, the agonist-bound conformation of US28 was stabilized and its structure was solved using the anti-US28 nanobody Nb7. Here we report the recognition of the constitutively active, apo-conformation of US28 by another nanobody VUN103. While the Nb7 intrabody selectively inhibits ligand-induced signaling, the VUN103 intrabody blocks constitutive signaling, indicating the existence of distinct US28 conformational states. By displacing Gαq protein, VUN103 prevents US28 signaling and reduces tumor spheroids growth. Overall, nanobodies specific for distinct GPCR conformational states, i.e. apo- and agonist-bound, can selectively target and discern functional consequences of ligand-dependent versus independent signaling. Various GPCRs display constitutive ligand-independent activity, but it remains unclear whether ligand-dependent and -independent conformations differ. Here the authors demonstrate the recognition and blocking of G protein recruitment of either the ligand-bound active, or the constitutively active apo-conformation of the viral GPCR US28 by different nanobodies that target similar intracellular loops of the receptor. |
| Databáze: | OpenAIRE |
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