Oxidative cyclization reagents reveal tryptophan cation–π interactions

Xiao Xie, Patrick J. Moon, Steven W. M. Crossley, Amanda J. Bischoff, Dan He, Gen Li, Nam Dao, Angel Gonzalez-Valero, Audrey G. Reeves, Jeffrey M. McKenna, Susanna K. Elledge, James A. Wells, F. Dean Toste () and Christopher J. Chang ()
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Xiao Xie: University of California, Berkeley
Patrick J. Moon: University of California, Berkeley
Steven W. M. Crossley: University of California, Berkeley
Amanda J. Bischoff: University of California, Berkeley
Dan He: University of California, Berkeley
Gen Li: University of California, Berkeley
Nam Dao: University of California, Berkeley
Angel Gonzalez-Valero: University of California, Berkeley
Audrey G. Reeves: University of California, Berkeley
Jeffrey M. McKenna: Novartis Institutes of Biomedical Research
Susanna K. Elledge: University of California San Francisco
James A. Wells: University of California San Francisco
F. Dean Toste: University of California, Berkeley
Christopher J. Chang: University of California, Berkeley

Nature, 2024, vol. 627, issue 8004, 680-687

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07140-6

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