9GFE

hRAR LBD protein in complex with AM580 agonist ligand and a stapled peptide

9GFE の概要

• エントリーDOI: 10.2210/pdb9gfe/pdb
• 分子名称: Retinoic acid receptor alpha, Stapled peptide-like ligand, 4-{[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)carbonyl]amino}benzoic acid, ... (4 entities in total)
• 機能のキーワード: hrar lbd protein, complex, stapled 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: 28136.95

構造登録者

Perdriau, C.,Luton, A.,Zimmeter, K.,Neuville, M.,Saragaglia, C.,Peluso-lltis, C.,Kauffmann, B.,Collie, G.,Rochel, N.,Guichard, G.,Pasco, M. (登録日: 2024-08-09, 公開日: 2025-01-22, 最終更新日: 2025-02-05)

主引用文献

Perdriau, C.,Luton, A.,Zimmeter, K.,Neuville, M.,Saragaglia, C.,Peluso-Iltis, C.,Osz, J.,Kauffmann, B.,Collie, G.W.,Rochel, N.,Guichard, G.,Pasco, M.
Guanidinium-Stapled Helical Peptides for Targeting Protein-Protein Interactions.
Angew.Chem.Int.Ed.Engl., 64:e202416348-e202416348, 2025

PubMed Abstract: Peptide stapling has emerged as a versatile approach in drug discovery to reinforce secondary structure elements especially α-helices and improve properties of linear bioactive peptides. Inspired by the prevalence of arginine in protein-protein and protein-DNA interfaces, we investigated guanidinium-stapling as a means to constrain helical peptides. Guanidinium stapling was readily achieved on solid support, utilizing two orthogonally protected lysine or unatural α-amino acid residues with an amino function. This method allows for easy modulation of the nature and size of the staple as well as helix propensity. Evaluating a set of guanidinium-stapled peptides for their interaction with different protein targets identified several binders with increased target affinity. X-ray structure determination of four complexes revealed that all stapled peptides adopt a helical conformation upon protein binding. Notably, the disubstituted guanidinium generally exhibits a distinct cis/trans conformation and, in one instance, retains a conserved hydrogen bond with the protein surface. By identifying, for the first time, the guanidinium moiety as an effective helical peptide stapling group, this research significantly expands the repertoire of α-helix stapling techniques for the creation of useful protein mimics.

PubMed: 39714600
DOI: 10.1002/anie.202416348

実験手法

X-RAY DIFFRACTION (1.583 Å)