ESRF Highlights 2023

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PRINCIPAL PUBLICATION AND AUTHORS

Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication, S. Postel (a), L. Wissler (a), C.A. Johansson (a), A. Gunnarsson (a), E. Gordon (b), B. Collins (c), M. Castaldo (b), C. Köhler (c), D. Öling (b), P. Johansson (a), L. Fröderberg Roth (b), B. Beinsteiner (d,e,f,g), I. Dainty (c), S. Delaney (c), B.P. Klaholz (d,e,f,g), I.M.L. Billas (d,e,f,g), K. Edman (a), Nat. Struct. Mol. Biol. 30, 286-295 (2023); https:/doi.org/10.1038/s41594-022-00914-4 (a) Mechanistic & Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg (Sweden) (b) Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg (Sweden) (c) Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg (Sweden) (d) Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, Institute of Genetics and of Molecular and Cellular Biology (IGBMC), Illkirch (France) (e) Université de Strasbourg, Illkirch (France) (f) Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch (France) (g) Centre National de la Recherche Scientifique (CNRS) UMR 7104, Illkirch (France)

REFERENCES

[1] G.N. Eick & J.W. Thornton, Mol. Cell. Endocrin. 334, 31-38, (2011). [2] G.K.A Hochberg et al., Nature 588, 503-508 (2020). [3] A. Tamrazi et al., Mol. Endocrin. 16, 2706-2719 (2002). [4] R.K. Bledsoe et al., Cell 110, 93-105 (2002).

The GR crystal quaternary structures provide a detailed view of the potential receptor residues involved in the allosteric communication between the DNA, ligand and coregulator binding sites. The domain arrangement is distinct from all previous multidomain nuclear receptor structures and highlights that although nuclear receptors largely operate using the same principles, the molecular details differ significantly. The GR quaternary structure provides a unique perspective on GR disease and will provide critical insight for future drug design.

Fig. 18: Comparison of how (a) velsecorat (magenta) and (b) fluticasone furoate (grey) binds within the ligand binding pocket of the GR LBD.