7SQB

PPAR gamma LBD bound to Inverse Agonist SR10221

7SQB の概要

• エントリーDOI: 10.2210/pdb7sqb/pdb
• 分子名称: 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)
• 機能のキーワード: inverse agonist, nuclear receptor, ligand binding domain, helix 12, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34422.74

構造登録者

Frkic, R.L.,Pederick, J.L.,Bruning, J.B. (登録日: 2021-11-05, 公開日: 2023-05-10, 最終更新日: 2023-10-25)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.6 Å)