9V8D

PPARgamma ligand-binding domain in complex with PG08

Summary for 9V8D

• Entry DOI: 10.2210/pdb9v8d/pdb
• Descriptor: Peroxisome proliferator-activated receptor gamma, PG08, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: nuclear receptor, de novo peptide, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 34404.95

Authors

Sigal, M.,Okada, C.,Katoh, T.,Suga, H.,Sengoku, T. (deposition date: 2025-05-29, release date: 2025-11-05, Last modification date: 2025-11-19)

Primary citation

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., 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

Experimental method

X-RAY DIFFRACTION (1.44 Å)