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

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  • Brian S. MacTavish

    (Scripps Research and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology)

  • Di Zhu

    (Scripps Research and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology)

  • Jinsai Shang

    (Scripps Research and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
    Guangzhou Medical University)

  • Qianzhen Shao

    (Vanderbilt University)

  • Yuanjun He

    (Scripps Research and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology)

  • Zhongyue J. Yang

    (Vanderbilt University
    Vanderbilt University
    Vanderbilt University
    Vanderbilt University)

  • Theodore M. Kamenecka

    (Scripps Research and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology)

  • Douglas J. Kojetin

    (Scripps Research and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
    Scripps Research and The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology
    Vanderbilt University
    Vanderbilt University)

Abstract

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 natively 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.

Suggested Citation

  • Brian S. MacTavish & Di Zhu & Jinsai Shang & Qianzhen Shao & Yuanjun He & Zhongyue J. Yang & Theodore M. Kamenecka & Douglas J. Kojetin, 2025. "Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57325-4
    DOI: 10.1038/s41467-025-57325-4
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    References listed on IDEAS

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    1. Tiffany Tate & Tina Xiang & Sarah E. Wobker & Mi Zhou & Xiao Chen & Hyunwoo Kim & Ekatherina Batourina & Chyuan-Sheng Lin & William Y. Kim & Chao Lu & James M. Mckiernan & Cathy Lee Mendelsohn, 2021. "Pparg signaling controls bladder cancer subtype and immune exclusion," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Richard Brust & Jinsai Shang & Jakob Fuhrmann & Sarah A. Mosure & Jared Bass & Andrew Cano & Zahra Heidari & Ian M. Chrisman & Michelle D. Nemetchek & Anne-Laure Blayo & Patrick R. Griffin & Theodore , 2018. "A structural mechanism for directing corepressor-selective inverse agonism of PPARγ," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    3. Xiao Hu & Mitchell A. Lazar, 1999. "The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors," Nature, Nature, vol. 402(6757), pages 93-96, November.
    4. Manav Korpal & Xiaoling Puyang & Zhenhua Jeremy Wu & Roland Seiler & Craig Furman & Htoo Zarni Oo & Michael Seiler & Sean Irwin & Vanitha Subramanian & Jaya Julie Joshi & Chris K. Wang & Victoria Rimk, 2017. "Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    5. Jinsai Shang & Sarah A. Mosure & Jie Zheng & Richard Brust & Jared Bass & Ashley Nichols & Laura A. Solt & Patrick R. Griffin & Douglas J. Kojetin, 2020. "A molecular switch regulating transcriptional repression and activation of PPARγ," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    6. Travis S. Hughes & Pankaj Kumar Giri & Ian Mitchelle S. de Vera & David P. Marciano & Dana S. Kuruvilla & Youseung Shin & Anne-Laure Blayo & Theodore M. Kamenecka & Thomas P. Burris & Patrick R. Griff, 2014. "An alternate binding site for PPARγ ligands," Nature Communications, Nature, vol. 5(1), pages 1-13, May.
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