A structural mechanism for directing corepressor-selective inverse agonism of PPARγ
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Abstract
Small chemical modifications can have significant effects on ligand efficacy and receptor activity, but the underlying structural mechanisms can be difficult to predict from static crystal structures alone. Here we show how a simple phenyl-to-pyridyl substitution between two common covalent orthosteric ligands targeting peroxisome proliferator-activated receptor (PPAR) gamma converts a transcriptionally neutral antagonist (GW9662) into a repressive inverse agonist (T0070907) relative to basal cellular activity. X-ray crystallography, molecular dynamics simulations, and mutagenesis coupled to activity assays reveal a water-mediated hydrogen bond network linking the T0070907 pyridyl group to Arg288 that is essential for corepressor-selective inverse agonism. NMR spectroscopy reveals that PPARγ exchanges between two long-lived conformations when bound to T0070907 but not GW9662, including a conformation that prepopulates a corepressor-bound state, priming PPARγ for high affinity corepressor binding. Our findings demonstrate that ligand engagement of Arg288 may provide routes for developing corepressor-selective repressive PPARγ ligands.
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A recent report supports the notion of different effects in artificial and native systems.
“A recent report supports the notion of different effects in artificial and”
From The Peroxisome Proliferator–Activated Receptor (PPAR)-γ Antagonist 2-Chloro-5-Nitro-N-Phenylbenzamide (GW9662) Triggers Perilipin 2 Expression via PPARδ and Induces Lipogenesis and Triglyceride Accumulation in Human THP-1 Macrophages (2020) · cites this paper as Brust et al., 2018
The Results section, “T0070907 lowers basal activity of PPARγ” (page unavailable), reports that qPCR measurements of PPARγ target genes in 3T3-L1 cells confirmed the ligand activity profiles, showing similar activating, neutral, and repressive trends. Rather than supporting different effects in the reporter and native-gene systems it tested, the paper reports similar trends. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredGW9662 covalently and irreversibly binds to the PPARγ ligand binding pocket, preventing activating ligand binding and interrupting PPARγ signal transduction.
“GW9662 has been shown to covalently and irreversibly bind to the PPARg ligand binding pocket (Leesnitzer et al., 2002;Brust et al., 2018).The binding of activating ligands is thereby prevented, and the signal transduction via PPARg is interrupted.”
From The Peroxisome Proliferator–Activated Receptor (PPAR)-γ Antagonist 2-Chloro-5-Nitro-N-Phenylbenzamide (GW9662) Triggers Perilipin 2 Expression via PPARδ and Induces Lipogenesis and Triglyceride Accumulation in Human THP-1 Macrophages (2020) · cites this paper as Brust et al., 2018
The Introduction and Discussion state that GW9662 covalently binds the orthosteric PPARγ pocket and blocks other orthosteric ligands, preventing activation by those agonists; the Discussion also calls it nondissociative. But the Results report that GW9662 did not significantly affect basal PPARγ transcription, so the broader claim that PPARγ signal transduction is interrupted overstates the source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe expression of PPARγ target genes FABP4 and CD36 tends to be increased by GW9662 in native adipocyte-like cells.
“Though GW9662 shows no effect in a cellbased full-length PPARg luciferase assay, the expression of the PPARg target genes FABP4 and CD36 tends to be increased by GW9662 in”
From The Peroxisome Proliferator–Activated Receptor (PPAR)-γ Antagonist 2-Chloro-5-Nitro-N-Phenylbenzamide (GW9662) Triggers Perilipin 2 Expression via PPARδ and Induces Lipogenesis and Triglyceride Accumulation in Human THP-1 Macrophages (2020) · cites this paper as Brust et al., 2018
The Methods section (‘3T3-L1 cell gene expression analysis’; page not specified) confirms that the study measured FABP4 and CD36 expression in 3T3-L1 cells after compound treatment. The Results section (‘T0070907 lowers basal activity of PPARγ’; page not specified) describes similar activating, neutral, and repressive trends in those cells, but characterizes GW9662 as having no significant effect in the transcription assay and does not state that it tended to increase either gene’s expression. (LLM, conf=0.78)
Experimental — accuracy not yet measuredT0070907 is a PPARγ antagonist with inverse agonist properties.
“we were interested in the PPARg antagonist 2-chloro-5-nitro-N-4-pyridinyl-benzamide (T0070907) (Lee et al., 2002) with inverse agonist properties (Lee et al., 2002;Brust et al., 2018) as an alternative.”
GW9662 shows no effect in a cell-based full-length PPARγ luciferase assay.
“Though GW9662 shows no effect in a cellbased full-length PPARg luciferase assay, the expression of the PPARg target genes FABP4 and CD36 tends to be increased by GW9662 in”
T0070907 has similar effects to GW9662 on RNA but not necessarily on the protein level.
“Furthermore, the structurally related antagonist or inverse agonist T0070907 (Lee et al., 2002;Hughes et al., 2014;Brust et al., 2018) might be a useful alternative depending on the experimental setup (Supplemental Fig. 13), as we observed similar effects to GW9662 on RNA but not necessarily on the protein level.”
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Schubert, M., Becher, S., Wallert, M., Maeß, M. B., Abhari, M., Rennert, K., Mosig, A. S., Große, S., Heller, R., Grün, M., et al. (2020) · Molecular Pharmacology · doi:10.1124/mol.119.117887 · Cited by 35 · see citing works
- Authors
- Brust, R., Shang, J., Fuhrmann, J., Mosure, S. A., Bass, J., Cano, A., Heidari, Z., Chrisman, I. M., Nemetchek, M. D., Blayo, A.-L., Griffin, P. R., Kamenecka, T. M., Hughes, T. S., & Kojetin, D. J.
- Affiliations
- Scripps Research Institute (US)
- University of Montana (US)
- Corresponding author
- Kojetin, Douglas J.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-11-08
- Volume
- 9
- Issue
- 1
- Pages
- 4687-4687
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6224492
- OpenAlex
- W2899394453
- Cited by
- 94
- References
- 0
- Citations by year
- 2026: 17 · 2025: 20 · 2024: 13 · 2023: 6 · 2022: 9 · 2021: 13 · 2020: 11 · 2019: 5
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Science Foundation (P20GM103546, 1157490)
- American Heart Association (16POST27780018)
- City University of New York
- National High Magnetic Field Laboratory (DMR-1157490, 1157490)
- Advanced Storage Research Consortium
- Thailand Science Research and Innovation
- National Institutes of Health (1s10od021832-01)
- National Institute of General Medical Sciences (P20GM103546)
- National Institute of Diabetes and Digestive and Kidney Diseases (R00DK103116, R01DK101871, R01DK105825, F32DK108442)
- Division of Materials Research (11‐57490, DMR 1157490)
- High Magnetic Field Laboratory, Chinese Academy of Sciences
- State of Florida
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- PPARγ, inverse agonism, GW9662, T0070907, hydrogen bond network, corepressor binding, ligand efficacy, nuclear receptor structure
- MeSH terms
- Anilides, Animals, Benzamides, Humans, Hydrogen Bonding, Ligands, Magnetic Resonance Spectroscopy, Protein Conformation, Pyridines, Water, Mutagenesis, 3T3-L1 Cells, PPAR gamma, Mice, Drug Inverse Agonism, Co-Repressor Proteins, HEK293 Cells
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