Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication.

Autor: Postel S; Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Wissler L; Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Johansson CA; Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Gunnarsson A; Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Gordon E; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Collins B; Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Castaldo M; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Köhler C; Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Öling D; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Johansson P; Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Fröderberg Roth L; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Beinsteiner B; Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, Institute of Genetics and of Molecular and Cellular Biology (IGBMC), Illkirch, France.; Université de Strasbourg, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch, France.; Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France., Dainty I; Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Delaney S; Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Klaholz BP; Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, Institute of Genetics and of Molecular and Cellular Biology (IGBMC), Illkirch, France.; Université de Strasbourg, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch, France.; Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France., Billas IML; Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, Institute of Genetics and of Molecular and Cellular Biology (IGBMC), Illkirch, France.; Université de Strasbourg, Illkirch, France.; Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch, France.; Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch, France., Edman K; Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden. karl.edman@astrazeneca.com.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2023 Mar; Vol. 30 (3), pp. 286-295. Date of Electronic Publication: 2023 Feb 06.
DOI: 10.1038/s41594-022-00914-4
Abstrakt: The glucocorticoid receptor (GR) is a ligand-activated transcription factor that binds DNA and assembles co-regulator complexes to regulate gene transcription. GR agonists are widely prescribed to people with inflammatory and autoimmune diseases. Here we present high-resolution, multidomain structures of GR in complex with ligand, DNA and co-regulator peptide. The structures reveal how the receptor forms an asymmetric dimer on the DNA and provide a detailed view of the domain interactions within and across the two monomers. Hydrogen-deuterium exchange and DNA-binding experiments demonstrate that ligand-dependent structural changes are communicated across the different domains in the full-length receptor. This study demonstrates how GR forms a distinct architecture on DNA and how signal transmission can be modulated by the ligand pharmacophore, provides a platform to build a new level of understanding of how receptor modifications can drive disease progression and offers key insight for future drug design.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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