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A molecular switch regulating transcriptional repression and activation of PPARγ.

<div class='caption-title'>PPARγ interacts with the transcriptional corepressor ID2 motif.</div>
<div class='caption-title'>Structure of PPARγ LBD bound to T0070907 and corepressor peptides.</div>
<div class='caption-title'>Structural changes between the repressive and active PPARγ LBD conformations.</div>
Shang J, Mosure SA, Zheng J, Brust R, Bass J, Nichols A, Solt LA, Griffin PR, Kojetin DJ
OpenAccess logo Nat Commun 11 956 (2020)
Related entries: 6onj, 6pdz

Cited: 26 times
EuropePMC logo PMID: 32075969

Abstract

Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations-supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations.

Articles - 6oni mentioned but not cited (5)

  1. A molecular switch regulating transcriptional repression and activation of PPARγ. Shang J, Mosure SA, Zheng J, Brust R, Bass J, Nichols A, Solt LA, Griffin PR, Kojetin DJ. Nat Commun 11 956 (2020)
  2. Systematic analyses on the potential immune and anti-inflammatory mechanisms of Shufeng Jiedu Capsule against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)-caused pneumonia. Tao Z, Zhang L, Friedemann T, Yang G, Li J, Wen Y, Wang J, Shen A. J Funct Foods 75 104243 (2020)
  3. Structural mechanism underlying ligand binding and activation of PPARγ. Shang J, Kojetin DJ. Structure 29 940-950.e4 (2021)
  4. research-article Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states. MacTavish B, Zhu D, Shang J, Shao Q, Yang ZJ, Kamenecka TM, Kojetin DJ. bioRxiv 2024.04.23.590805 (2024)
  5. Unanticipated mechanisms of covalent inhibitor and synthetic ligand cobinding to PPARγ. Shang J, Kojetin DJ. bioRxiv 2024.05.15.594037 (2024)


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  2. Cannabinoids and Neurogenesis: The Promised Solution for Neurodegeneration? Valeri A, Mazzon E. Molecules 26 6313 (2021)
  3. PPARγ Modulators in Lung Cancer: Molecular Mechanisms, Clinical Prospects, and Challenges. Zhang J, Tang M, Shang J. Biomolecules 14 190 (2024)

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  2. Structural basis for heme-dependent NCoR binding to the transcriptional repressor REV-ERBβ. Mosure SA, Strutzenberg TS, Shang J, Munoz-Tello P, Solt LA, Griffin PR, Kojetin DJ. Sci Adv 7 eabc6479 (2021)
  3. CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition. Musicant AM, Parag-Sharma K, Gong W, Sengupta M, Chatterjee A, Henry EC, Tsai YH, Hayward MC, Sheth S, Betancourt R, Hackman TG, Padilla RJ, Parker JS, Giudice J, Flaveny CA, Hayes DN, Amelio AL. Cell Rep 34 108768 (2021)
  4. A structural mechanism of nuclear receptor biased agonism. Nemetchek MD, Chrisman IM, Rayl ML, Voss AH, Hughes TS. Proc Natl Acad Sci U S A 119 e2215333119 (2022)
  5. Cooperativity as quantification and optimization paradigm for nuclear receptor modulators. de Vink PJ, Koops AA, D'Arrigo G, Cruciani G, Spyrakis F, Brunsveld L. Chem Sci 13 2744-2752 (2022)
  6. Targeting the Alternative Vitamin E Metabolite Binding Site Enables Noncanonical PPARγ Modulation. Arifi S, Marschner JA, Pollinger J, Isigkeit L, Heitel P, Kaiser A, Obeser L, Höfner G, Proschak E, Knapp S, Chaikuad A, Heering J, Merk D. J Am Chem Soc 145 14802-14810 (2023)
  7. Loss of hepatic FTCD promotes lipid accumulation and hepatocarcinogenesis by upregulating PPARγ and SREBP2. Wang S, Zhou Y, Yu R, Ling J, Li B, Yang C, Cheng Z, Qian R, Lin Z, Yu C, Zheng J, Zheng X, Jia Q, Wu W, Wu Q, Chen M, Yuan S, Dong W, Shi Y, Jansen R, Yang C, Hao Y, Yao M, Qin W, Jin H. JHEP Rep 5 100843 (2023)
  8. Biochemical and structural basis for the pharmacological inhibition of nuclear hormone receptor PPARγ by inverse agonists. Irwin S, Karr C, Furman C, Tsai J, Gee P, Banka D, Wibowo AS, Dementiev AA, O'Shea M, Yang J, Lowe J, Mitchell L, Ruppel S, Fekkes P, Zhu P, Korpal M, Larsen NA. J Biol Chem 298 102539 (2022)
  9. Discovery and Structure-Based Design of Potent Covalent PPARγ Inverse-Agonists BAY-4931 and BAY-0069. Orsi DL, Pook E, Bräuer N, Friberg A, Lienau P, Lemke CT, Stellfeld T, Brüggemeier U, Pütter V, Meyer H, Baco M, Tang S, Cherniack AD, Westlake L, Bender SA, Kocak M, Strathdee CA, Meyerson M, Eis K, Goldstein JT. J Med Chem 65 14843-14863 (2022)
  10. Ligand-induced shifts in conformational ensembles that describe transcriptional activation. Khan SH, Braet SM, Koehler SJ, Elacqua E, Anand GS, Okafor CD. Elife 11 e80140 (2022)
  11. Molecular dynamics of the ERRγ ligand-binding domain bound with agonist and inverse agonist. Sasidharan S, Radhakrishnan K, Lee JY, Saudagar P, Gosu V, Shin D. PLoS One 18 e0283364 (2023)
  12. Sex-Specific Effects of THRβ Signaling on Metabolic Responses to High Fat Diet in Mice. Muralidharan A, Gomez GA, Kesavan C, Pourteymoor S, Larkin D, Tambunan W, Sechriest VF, Mohan S. Endocrinology 165 bqae075 (2024)
  13. Structural overview and perspectives of the nuclear receptors, a major family as the direct targets for small-molecule drugs. Li F, Song C, Zhang Y, Wu D. Acta Biochim Biophys Sin (Shanghai) 54 12-24 (2022)
  14. Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR. Garcia-Maldonado E, Huber AD, Chai SC, Nithianantham S, Li Y, Wu J, Poudel S, Miller DJ, Seetharaman J, Chen T. Nat Commun 15 4054 (2024)
  15. Dysregulation of the Amniotic PPARγ Pathway by Phthalates: Modulation of the Anti-Inflammatory Activity of PPARγ in Human Fetal Membranes. Antoine A, De Sousa Do Outeiro C, Charnay C, Belville C, Henrioux F, Gallot D, Blanchon L, Minet-Quinard R, Sapin V. Life (Basel) 12 544 (2022)
  16. Effects of ethanol or ethylene glycol exposure on PPARγ and aromatase expression in adipose tissue. Ardenkjær-Skinnerup J, Saar D, Christiansen S, Svingen T, Hadrup N, Brown KA, Emanuelli B, Kragelund BB, Ravn-Haren G, Vogel U. Biochem Biophys Rep 38 101742 (2024)
  17. Rational design of stapled helical peptides as antidiabetic PPARγ antagonists to target coactivator site by decreasing unfavorable entropy penalty instead of increasing favorable enthalpy contribution. Zhang Y, Wang J, Li W, Guo Y. Eur Biophys J 51 535-543 (2022)
  18. Two steps, one ligand: How PPARγ binds small-molecule agonists. Siclari JJ, Gardner KH. Structure 29 935-936 (2021)


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