Mays, Suzanne G.Stec, JózefLiu, XuD'Agostino, Emma H.Whitby, Richard J.Ortlund, Eric A.2022-06-142022-06-142020Mays SG, Stec J, Liu X, D'Agostino EH, Whitby RJ, Ortlund EA. Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist. Sci Rep. 2020 Dec 17;10(1):22279. DOI:10.1038/s41598-020-79251-92045-2322http://hdl.handle.net/10230/53487Chirality is an important consideration in drug development: it can influence recognition of the intended target, pharmacokinetics, and off-target effects. Here, we investigate how chirality affects the activity and mechanism of action of RJW100, a racemic agonist of the nuclear receptors liver receptor homolog-1 (LRH-1) and steroidogenic factor-1 (SF-1). LRH-1 and SF-1 modulators are highly sought as treatments for metabolic and neoplastic diseases, and RJW100 has one of the few scaffolds shown to activate them. However, enantiomer-specific effects on receptor activation are poorly understood. We show that the enantiomers have similar binding affinities, but RR-RJW100 stabilizes both receptors and is 46% more active than SS-RJW100 in LRH-1 luciferase reporter assays. We present an LRH-1 crystal structure that illuminates striking mechanistic differences: SS-RJW100 adopts multiple configurations in the pocket and fails to make an interaction critical for activation by RR-RJW100. In molecular dynamics simulations, SS-RJW100 attenuates intramolecular signalling important for coregulator recruitment, consistent with previous observations that it weakly recruits coregulators in vitro. These studies provide a rationale for pursuing enantiomerically pure RJW100 derivatives: they establish RR-RJW100 as the stronger LRH-1 agonist and identify a potential for optimizing the SS-RJW100 scaffold for antagonist design.application/pdfeng© Suzanne G. Mays et al 2020. 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 madeQuiralitatMedicaments -- DesenvolupamentFetge -- Malaltiesinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41598-020-79251-9info:eu-repo/semantics/openAccess