9V8D

PPARgamma ligand-binding domain in complex with PG08

9V8D の概要

• エントリーDOI: 10.2210/pdb9v8d/pdb
• 分子名称: Peroxisome proliferator-activated receptor gamma, PG08, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• 機能のキーワード: nuclear receptor, de novo peptide, transcription
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34404.95

構造登録者

Sigal, M.,Okada, C.,Katoh, T.,Suga, H.,Sengoku, T. (登録日: 2025-05-29, 公開日: 2025-11-05, 最終更新日: 2025-12-03)

主引用文献

Sigal, M.,Egner, M.,Okada, C.,Merk, D.,Sengoku, T.,Katoh, T.,Suga, H.
De Novo Discovery of alpha , alpha-Disubstituted alpha-amino Acid-Containing alpha-helical Peptides as Competitive PPAR gamma PPI Inhibitors.
J.Am.Chem.Soc., 147:42607-42617, 2025

PubMed Abstract: α,α-Disubstituted α-amino acids (dαAAs) are important building blocks for peptidomimetics as they are strong inducers of helicity and protect against proteolytic degradation. However, discovery of dαAA-containing peptides with genetically encoded libraries is limited due to their poor incorporation efficiency. Here, we report the optimized ribosomal incorporation of multiple achiral dαAAs into peptide libraries and their application to high-throughput (>10 members) affinity selection against the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ). This dαAA-based screening methodology discovered potent linear and macrocyclic α-helical peptides with low-to-sub nanomolar binding affinities. Hit peptides were proteolytically stable in serum and cell permeable, allowing for antagonism of PPARγ. X-ray crystallography revealed that dαAA-containing peptides bound at the α-helical protein-protein interaction (PPI) interface via an α-helical conformation. This work validates the potential of a dαAA-based, α-helical discovery platform, providing access to new chemical and conformational space to identify novel α-helical peptidomimetics.

PubMed: 41188059
DOI: 10.1021/jacs.5c13803

実験手法

X-RAY DIFFRACTION (1.44 Å)