5JM4

Crystal structure of 14-3-3zeta in complex with a cyclic peptide involving an adamantyl and a dicarboxy side chain

5JM4 の概要

• エントリーDOI: 10.2210/pdb5jm4/pdb
• 関連するPDBエントリー: 4N7G 4N84
• 分子名称: 14-3-3 protein zeta/delta, GLN-GLY-MKD-ANG-ASP-MKD-LEU-ASP-LEU-ALA-CLU, BENZOIC ACID, ... (4 entities in total)
• 機能のキーワード: peptidomimetic, ppi inhibitor, macrocycle, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 55687.07

構造登録者

Bier, D.,Krueger, D.,Glas, A.,Wallraven, K.,Ottmann, C.,Hennig, S.,Grossmann, T. (登録日: 2016-04-28, 公開日: 2017-05-10, 最終更新日: 2024-01-10)

主引用文献

Kruger, D.M.,Glas, A.,Bier, D.,Pospiech, N.,Wallraven, K.,Dietrich, L.,Ottmann, C.,Koch, O.,Hennig, S.,Grossmann, T.N.
Structure-Based Design of Non-natural Macrocyclic Peptides That Inhibit Protein-Protein Interactions.
J. Med. Chem., 60:8982-8988, 2017

PubMed Abstract: Macrocyclic peptides can interfere with challenging biomolecular targets including protein-protein interactions. Whereas there are various approaches that facilitate the identification of peptide-derived ligands, their evolution into higher affinity binders remains a major hurdle. We report a virtual screen based on molecular docking that allows the affinity maturation of macrocyclic peptides taking non-natural amino acids into consideration. These macrocycles bear large and flexible substituents that usually complicate the use of docking approaches. A virtual library containing more than 1400 structures was screened against the target focusing on docking poses with the core structure resembling a known bioactive conformation. Based on this screen, a macrocyclic peptide 22 involving two non-natural amino acids was evolved showing increased target affinity and biological activity. Predicted binding modes were verified by X-ray crystallography. The presented workflow allows the screening of large macrocyclic peptides with diverse modifications thereby expanding the accessible chemical space and reducing synthetic efforts.

PubMed: 29028171
DOI: 10.1021/acs.jmedchem.7b01221

実験手法

X-RAY DIFFRACTION (2.34 Å)