6U22

Crystal structure of SFTI-triazole inhibitor in complex with beta-trypsin

6U22 の概要

• エントリーDOI: 10.2210/pdb6u22/pdb
• 分子名称: Cationic trypsin, GLY-ARG-ALA-THR-LYS-SER-ILE-PRO-PRO-ILE-ALA-PHE-PRO-ASP, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: triazole, peptidomimetic, biosynthetic protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• 由来する生物種: Bos taurus (Bovine); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 24919.16

構造登録者

White, A.M.,King, G.J.,Durek, T.,Craik, D.J. (登録日: 2019-08-19, 公開日: 2020-07-01, 最終更新日: 2024-11-06)

主引用文献

White, A.M.,de Veer, S.J.,Wu, G.,Harvey, P.J.,Yap, K.,King, G.J.,Swedberg, J.E.,Wang, C.K.,Law, R.H.P.,Durek, T.,Craik, D.J.
Application and Structural Analysis of Triazole-Bridged Disulfide Mimetics in Cyclic Peptides.
Angew.Chem.Int.Ed.Engl., 59:11273-11277, 2020

PubMed Abstract: Ruthenium-catalysed azide-alkyne cycloaddition (RuAAC) provides access to 1,5-disubstituted 1,2,3-triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross-linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor-1. NMR and X-ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole-bridged peptides also displayed superior half-lives in liver S9 stability assays compared to disulfide-bridged peptides. This work establishes a foundation for the application of 1,5-disubstituted 1,2,3-triazoles as disulfide mimetics.

PubMed: 32270580
DOI: 10.1002/anie.202003435

実験手法

X-RAY DIFFRACTION (1.42 Å)