6VXY

Triazole bridged SFTI1 inhibitor in complex with beta-trypsin

Summary for 6VXY

• Entry DOI: 10.2210/pdb6vxy/pdb
• Related: 6U22 6U24
• Related PRD ID: PRD_002374
• Descriptor: Cationic trypsin, SFTI1 inhibitor GLY-ARG-GLY-THR-LYS-SER-ILE-PRO-PRO-ILE-ALA-PHE-PRO-ASP, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: triazole, peptidomimetic, biosynthetic protein
• Biological source: Bos taurus (Bovine); More
• Total number of polymer chains: 2
• Total formula weight: 24905.13

Authors

White, A.M.,King, G.J.,Durek, T.,Craik, D.J. (deposition date: 2020-02-25, release date: 2020-07-01, Last modification date: 2024-10-23)

Primary citation

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., 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

Experimental method

X-RAY DIFFRACTION (1.398 Å)