Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

Oxidative cyclization reagents reveal tryptophan cation-π interactions.

Xie, Xiao, Moon, Patrick J., Crossley, Steven W. M., Elledge, Susanna K., Bischoff, Amanda J., Reeves, Audrey G., Gonzalez-Valero, Angel, He, Dan, Dao, Nam, Li, Gen, McKenna, Jeffrey, Wells, James A., Toste, F. Dean and Chang, Christopher J. (2024) Oxidative cyclization reagents reveal tryptophan cation-π interactions. Nature. ISSN 1476-4687

Abstract

Methods for selective covalent modification of amino acids on proteins can enable a diverse array of applications, spanning probes and modulators of protein function to proteomics1-3. Owing to their high nucleophilicity, cysteine and lysine residues are the most common points of attachment for protein bioconjugation chemistry through acid-base reactivity3,4. Here we report a redox-based strategy for bioconjugation of tryptophan, the rarest amino acid, using oxaziridine reagents that mimic oxidative cyclization reactions in indole-based alkaloid biosynthetic pathways to achieve highly efficient and specific tryptophan labelling. We establish the broad use of this method, termed tryptophan chemical ligation by cyclization (Trp-CLiC), for selectively appending payloads to tryptophan residues on peptides and proteins with reaction rates that rival traditional click reactions and enabling global profiling of hyper-reactive tryptophan sites across whole proteomes. Notably, these reagents reveal a systematic map of tryptophan residues that participate in cation-π interactions, including functional sites that can regulate protein-mediated phase-separation processes.

Item Type: Article
Date Deposited: 28 Mar 2024 00:46
Last Modified: 28 Mar 2024 00:46
URI: https://oak.novartis.com/id/eprint/46580

Search