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Ligand Binding Mechanism in Steroid Receptors: From Conserved Plasticity to Differential Evolutionary Constraints.

Edman K, Hosseini A, Bjursell MK, Aagaard A, Wissler L, Gunnarsson A, Kaminski T, Köhler C, Bäckström S, Jensen TJ, Cavallin A, Karlsson U, Nilsson E, Lecina D, Takahashi R, Grebner C, Geschwindner S, Lepistö M, Hogner AC, Guallar V
Structure 23 2280-2290 (2015)
Related entries: 4udb, 4udc, 4udd

Cited: 38 times
EuropePMC logo PMID: 26602186

Abstract

Steroid receptor drugs have been available for more than half a century, but details of the ligand binding mechanism have remained elusive. We solved X-ray structures of the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at the helix 6-7 region that extends the ligand binding pocket toward the receptor surface. Since none of the endogenous ligands exploit this region, we hypothesized that it constitutes an integral part of the binding event. Extensive all-atom unbiased ligand exit and entrance simulations corroborate a ligand binding pathway that gives the observed structural plasticity a key functional role. Kinetic measurements reveal that the receptor residence time correlates with structural rearrangements observed in both structures and simulations. Ultimately, our findings reveal why nature has conserved the capacity to open up this region, and highlight how differences in the details of the ligand entry process result in differential evolutionary constraints across the steroid receptors.

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  1. Getting Docking into Shape Using Negative Image-Based Rescoring. Kurkinen ST, Lätti S, Pentikäinen OT, Postila PA. J Chem Inf Model 59 3584-3599 (2019)
  2. Preclinical pharmacology of AZD9977: A novel mineralocorticoid receptor modulator separating organ protection from effects on electrolyte excretion. Bamberg K, Johansson U, Edman K, William-Olsson L, Myhre S, Gunnarsson A, Geschwindner S, Aagaard A, Björnson Granqvist A, Jaisser F, Huang Y, Granberg KL, Jansson-Löfmark R, Hartleib-Geschwindner J. PLoS One 13 e0193380 (2018)


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  2. Saponins as modulators of nuclear receptors. Zhang T, Zhong S, Li T, Zhang J. Crit Rev Food Sci Nutr 60 94-107 (2020)
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  4. Adaptive simulations, towards interactive protein-ligand modeling. Lecina D, Gilabert JF, Guallar V. Sci Rep 7 8466 (2017)
  5. Computational insight of dexamethasone against potential targets of SARS-CoV-2. Fadaka AO, Sibuyi NRS, Madiehe AM, Meyer M. J Biomol Struct Dyn 40 875-885 (2022)
  6. Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment. Liu X, Wang Y, Gutierrez JS, Damsker JM, Nagaraju K, Hoffman EP, Ortlund EA. Proc Natl Acad Sci U S A 117 24285-24293 (2020)
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  10. Structural Basis of Altered Potency and Efficacy Displayed by a Major in Vivo Metabolite of the Antidiabetic PPARγ Drug Pioglitazone. Mosure SA, Shang J, Eberhardt J, Brust R, Zheng J, Griffin PR, Forli S, Kojetin DJ. J Med Chem 62 2008-2023 (2019)
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  13. Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators. Munier CC, De Maria L, Edman K, Gunnarsson A, Longo M, MacKintosh C, Patel S, Snijder A, Wissler L, Brunsveld L, Ottmann C, Perry MWD. J Biol Chem 296 100551 (2021)
  14. Molecular basis of crosstalk in nuclear receptors: heterodimerization between PXR and CAR and the implication in gene regulation. Bwayi MN, Garcia-Maldonado E, Chai SC, Xie B, Chodankar S, Huber AD, Wu J, Annu K, Wright WC, Lee HM, Seetharaman J, Wang J, Buchman CD, Peng J, Chen T. Nucleic Acids Res 50 3254-3275 (2022)
  15. Atomistic simulations shed new light on the activation mechanisms of RORγ and classify it as Type III nuclear hormone receptor regarding ligand-binding paths. Saen-Oon S, Lozoya E, Segarra V, Guallar V, Soliva R. Sci Rep 9 17249 (2019)
  16. Exploring Binding Mechanisms in Nuclear Hormone Receptors by Monte Carlo and X-ray-derived Motions. Grebner C, Lecina D, Gil V, Ulander J, Hansson P, Dellsen A, Tyrchan C, Edman K, Hogner A, Guallar V. Biophys J 112 1147-1156 (2017)
  17. Spontaneous Ligand Access Events to Membrane-Bound Cytochrome P450 2D6 Sampled at Atomic Resolution. Fischer A, Smieško M. Sci Rep 9 16411 (2019)
  18. A new p65 isoform that bind the glucocorticoid hormone and is expressed in inflammation liver diseases and COVID-19. Spinelli G, Biddeci G, Artale A, Valentino F, Tarantino G, Gallo G, Gianguzza F, Conaldi PG, Corrao S, Gervasi F, Aronica TS, Di Leonardo A, Duro G, Di Blasi F. Sci Rep 11 22913 (2021)
  19. GPathFinder: Identification of Ligand-Binding Pathways by a Multi-Objective Genetic Algorithm. Sánchez-Aparicio JE, Sciortino G, Herrmannsdoerfer DV, Chueca PO, Pedregal JR, Maréchal JD. Int J Mol Sci 20 E3155 (2019)
  20. Mechanisms of a Sustained Anti-inflammatory Drug Response in Alveolar Macrophages Unraveled with Mathematical Modeling. Nyman E, Lindh M, Lövfors W, Simonsson C, Persson A, Eklund D, Bäckström E, Fridén M, Cedersund G. CPT Pharmacometrics Syst Pharmacol 9 707-717 (2020)
  21. Multifunctional Analysis of Chia Seed (Salvia hispanica L.) Bioactive Peptides Using Peptidomics and Molecular Dynamics Simulations Approaches. Aguilar-Toalá JE, Vidal-Limon A, Liceaga AM. Int J Mol Sci 23 7288 (2022)
  22. Structure-Based Drug Design of Mineralocorticoid Receptor Antagonists to Explore Oxosteroid Receptor Selectivity. Nordqvist A, O'Mahony G, Fridén-Saxin M, Fredenwall M, Hogner A, Granberg KL, Aagaard A, Bäckström S, Gunnarsson A, Kaminski T, Xue Y, Dellsén A, Hansson E, Hansson P, Ivarsson I, Karlsson U, Bamberg K, Hermansson M, Georgsson J, Lindmark B, Edman K. ChemMedChem 12 50-65 (2017)
  23. Backbone 1H, 13C, and 15N resonance assignments of the ligand binding domain of the human wildtype glucocorticoid receptor and the F602S mutant variant. Köhler C, Carlström G, Tångefjord S, Papavoine T, Lepistö M, Edman K, Akke M. Biomol NMR Assign 12 263-268 (2018)
  24. Discovery of new selective glucocorticoid receptor agonist leads. Berger M, Rehwinkel H, Schmees N, Schäcke H, Edman K, Wissler L, Reichel A, Jaroch S. Bioorg Med Chem Lett 27 437-442 (2017)
  25. Novel selective glucocorticoid receptor agonists (SEGRAs) with a covalent warhead for long-lasting inhibition. Ryabtsova O, Joossens J, Van Der Veken P, Vanden Berghe W, Augustyns K, De Winter H. Bioorg Med Chem Lett 26 5032-5038 (2016)
  26. Physics-Based Visual Characterization of Molecular Interaction Forces. Hermosilla P, Estrada J, Guallar V, Ropinski T, Vinacua A, Vazquez PP. IEEE Trans Vis Comput Graph 23 731-740 (2017)
  27. Quaternary glucocorticoid receptor structure highlights allosteric interdomain communication. Postel S, Wissler L, Johansson CA, Gunnarsson A, Gordon E, Collins B, Castaldo M, Köhler C, Öling D, Johansson P, Fröderberg Roth L, Beinsteiner B, Dainty I, Delaney S, Klaholz BP, Billas IML, Edman K. Nat Struct Mol Biol 30 286-295 (2023)
  28. The Role of Conformational Dynamics and Allostery in the Control of Distinct Efficacies of Agonists to the Glucocorticoid Receptor. Shi Y, Cao S, Ni D, Fan J, Lu S, Xue M. Front Mol Biosci 9 933676 (2022)
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  30. Insights into peculiar fungal LPMO family members holding a short C-terminal sequence reminiscent of phosphate binding motifs. Reyre JL, Grisel S, Haon M, Xiang R, Gaillard JC, Armengaud J, Guallar V, Margeot A, Arragain S, Berrin JG, Bissaro B. Sci Rep 13 11586 (2023)
  31. Stereoisomers of an Aryl Pyrazole Glucocorticoid Receptor Agonist Scaffold Elicit Differing Anti-inflammatory Responses. Lato AM, Burke SJ, Ducote MP, Kennedy BJ, Collier JJ, Campagna SR. ACS Med Chem Lett 13 1493-1499 (2022)


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