6VC2

LRH-1 bound to SS-RJW100 and a fragment of the Tif2 Coactivator

Summary for 6VC2

• Entry DOI: 10.2210/pdb6vc2/pdb
• Descriptor: Nuclear receptor subfamily 5 group A member 2, Nuclear receptor coactivator 2, (1S,3aS,6aS)-5-hexyl-4-phenyl-3a-(1-phenylethenyl)-1,2,3,3a,6,6a-hexahydropentalen-1-ol, ... (4 entities in total)
• Functional Keywords: nuclear hormone receptor, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 30527.30

Authors

Mays, S.G.,Ortlund, E.A. (deposition date: 2019-12-20, release date: 2020-12-23, Last modification date: 2023-10-11)

Primary citation

Mays, S.G.,Stec, J.,Liu, X.,D'Agostino, E.H.,Whitby, R.J.,Ortlund, E.A.
Enantiomer-specific activities of an LRH-1 and SF-1 dual agonist.
Sci Rep, 10:22279-22279, 2020

PubMed Abstract: Chirality 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.

PubMed: 33335203
DOI: 10.1038/s41598-020-79251-9

Experimental method

X-RAY DIFFRACTION (1.697 Å)