A structural mechanism of nuclear receptor biased agonism

Nemetchek, Michelle D.; Chrisman, Ian M.; Rayl, Mariah; Voss, Andrew A.; Hughes, Travis

doi:10.1016/j.bpj.2022.11.2503

Cited by 1 publication

(1 citation statement)

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“…Inverse agonists stabilize an LBD conformation that promotes interaction with corepressor proteins over coactivators, leading to transcriptional repression of gene expression. These liganddependent activities, which result in distinct coregulator recruitment and transcriptional outcomes, are known as ligand bias 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states

MacTavish,

Zhu,

Shang

et al. 2024

Preprint

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Nuclear receptors (NRs) are thought to dynamically alternate between transcriptionally active and repressive conformations, which are stabilized upon ligand binding. Most NR ligand series exhibit limited bias, primarily consisting of transcriptionally active agonists or neutral antagonists, but not repressive inverse agonists—a limitation that restricts understanding of the functional NR conformational ensemble. Here, we report a NR ligand series for peroxisome proliferator-activated receptor gamma (PPARγ) that spans a pharmacological spectrum from repression (inverse agonism) to activation (agonism) where subtle structural modifications switch compound activity. While crystal structures provide snapshots of the fully repressive state, NMR spectroscopy and conformation-activity relationship analysis reveals that compounds within the series shift the PPARγ conformational ensemble between transcriptionally active and repressive conformations that are populated in the apo/ligand-free ensemble. Our findings reveal a molecular framework for minimal chemical modifications that enhance PPARγ inverse agonism and elucidate their influence on the dynamic PPARγ conformational ensemble.

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Section: Introductionmentioning

confidence: 99%