Oxidative cyclization reagents reveal tryptophan cation-π interactions

• 成果类型: Article
• 署名作者: Xie, Xiao; Moon, Patrick J.; Crossley, Steven W. M.; Bischoff, Amanda J.; He, Dan; Li, Gen; Dao, Nam; Gonzalez-Valero, Angel; Reeves, Audrey G.; McKenna, Jeffrey M.; Elledge, Susanna K.; Wells, James A.; Toste, F. Dean; Chang, Christopher J.
• 署名单位: University of California System; University of California Berkeley; University of California System; University of California Berkeley; University of California System; University of California Berkeley; United States Department of Energy (DOE); Lawrence Berkeley National Laboratory; Novartis; Novartis USA; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4629
• DOI: 10.1038/s41586-024-07140-6
• 发表日期: 2024-03-21
• 页码: 680-+
• 关键词: residues; nucleophosmin; inhibitors; peptides; proteins

摘要

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 proteomics(1, 2-3). Owing to their high nucleophilicity, cysteine and lysine residues are the most common points of attachment for protein bioconjugation chemistry through acid-base reactivity(3,4). 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- interactions, including functional sites that can regulate protein-mediated phase-separation processes.