6XZH

Structure of zVDR LBD-Calcitriol in complex with chimera 10

Summary for 6XZH

• Entry DOI: 10.2210/pdb6xzh/pdb
• Descriptor: Vitamin D3 receptor A, ARG-HIS-LYS-ILE-URL-URK-URL-LEU-GLN, 5-{2-[1-(5-HYDROXY-1,5-DIMETHYL-HEXYL)-7A-METHYL-OCTAHYDRO-INDEN-4-YLIDENE]-ETHYLIDENE}-4-METHYLENE-CYCLOHEXANE-1,3-DIOL, ... (4 entities in total)
• Functional Keywords: nuclear receptor, foldamer, helix mimicry, protein-protein interaction, gene regulation
• Biological source: Danio rerio (Zebrafish); More
• Total number of polymer chains: 2
• Total formula weight: 35716.91

Authors

Buratto, J.,Belorusova, A.Y.,Rochel, N.,Guichard, G. (deposition date: 2020-02-04, release date: 2021-02-17, Last modification date: 2024-10-16)

Primary citation

Cussol, L.,Mauran-Ambrosino, L.,Buratto, J.,Belorusova, A.Y.,Neuville, M.,Osz, J.,Fribourg, S.,Fremaux, J.,Dolain, C.,Goudreau, S.R.,Rochel, N.,Guichard, G.
Structural Basis for alpha-Helix Mimicry and Inhibition of Protein-Protein Interactions with Oligourea Foldamers.
Angew.Chem.Int.Ed.Engl., 60:2296-2303, 2021

PubMed Abstract: Efficient optimization of a peptide lead into a drug candidate frequently needs further transformation to augment properties such as bioavailability. Among the different options, foldamers, which are sequence-based oligomers with precise folded conformation, have emerged as a promising technology. We introduce oligourea foldamers to reduce the peptide character of inhibitors of protein-protein interactions (PPI). However, the precise design of such mimics is currently limited by the lack of structural information on how these foldamers adapt to protein surfaces. We report a collection of X-ray structures of peptide-oligourea hybrids in complex with ubiquitin ligase MDM2 and vitamin D receptor and show how such hybrid oligomers can be designed to bind with high affinity to protein targets. This work should enable the generation of more effective foldamer-based disruptors of PPIs in the context of peptide lead optimization.

PubMed: 32935897
DOI: 10.1002/anie.202008992

Experimental method

X-RAY DIFFRACTION (2.372 Å)