7SQB

PPAR gamma LBD bound to Inverse Agonist SR10221

Summary for 7SQB

• Entry DOI: 10.2210/pdb7sqb/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, (2S)-2-{5-[(5-{[(1S)-1-(4-tert-butylphenyl)ethyl]carbamoyl}-2,3-dimethyl-1H-indol-1-yl)methyl]-2-chlorophenoxy}propanoic acid (3 entities in total)
• Functional Keywords: inverse agonist, nuclear receptor, ligand binding domain, helix 12, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34422.74

Authors

Frkic, R.L.,Pederick, J.L.,Bruning, J.B. (deposition date: 2021-11-05, release date: 2023-05-10, Last modification date: 2023-10-25)

Primary citation

Frkic, R.L.,Pederick, J.L.,Horsfall, A.J.,Jovcevski, B.,Crame, E.E.,Kowalczyk, W.,Pukala, T.L.,Chang, M.R.,Zheng, J.,Blayo, A.L.,Abell, A.D.,Kamenecka, T.M.,Harbort, J.S.,Harmer, J.R.,Griffin, P.R.,Bruning, J.B.
PPAR gamma Corepression Involves Alternate Ligand Conformation and Inflation of H12 Ensembles.
Acs Chem.Biol., 18:1115-1123, 2023

PubMed Abstract: Inverse agonists of peroxisome proliferator activated receptor γ (PPARγ) have emerged as safer alternatives to full agonists for their reduced side effects while still maintaining impressive insulin-sensitizing properties. To shed light on their molecular mechanism, we characterized the interaction of the PPARγ ligand binding domain with SR10221. X-ray crystallography revealed a novel binding mode of SR10221 in the presence of a transcriptionally repressing corepressor peptide, resulting in much greater destabilization of the activation helix, H12, than without corepressor peptide. Electron paramagnetic resonance provided in-solution complementary protein dynamic data, which revealed that for SR10221-bound PPARγ, H12 adopts a plethora of conformations in the presence of corepressor peptide. Together, this provides the first direct evidence for corepressor-driven ligand conformation for PPARγ and will allow the development of safer and more effective insulin sensitizers suitable for clinical use.

PubMed: 37146157
DOI: 10.1021/acschembio.2c00917

Experimental method

X-RAY DIFFRACTION (2.6 Å)