High-throughput protein target mapping enables accelerated bioactivity discovery for ToxCast and PFAS compounds

• 成果类型: Article
• 署名作者: Yang, Diwen; Wang, Xiaoyun; Liu, Jiabao; Gong, Yufeng; Nair, Pranav; Sun, Jianxian; Qian, Xing; Cui, Jingyuan; Zeng, Hong; Dong, Aiping; Harding, Rachel J.; Burgess-Brown, Nicola; Beyett, Tyler S.; Song, Datong; Krause, Henry M.; Diamond, Miriam L.; Bolhuis, Derek L.; Brown, Nicholas G.; Arrowsmith, Cheryl H.; Edwards, Aled M.; Halabelian, Levon; Peng, Hui
• 署名单位: University of Toronto; University Toronto Scarborough; University of Toronto; University of Toronto; University of Toronto; Structural Genomics Consortium; University of Toronto; University of Toronto; University of London; University College London; Emory University; University of Toronto; University of Toronto; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; University of Toronto
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2515940123
• 发表日期: 2026-06-23
• 页码: e2515940123
• 关键词: protein-ligand interaction; ToxCast; pfas; PERFLUORINATED COMPOUNDS; PERFLUOROALKYL ACIDS; binding; toxicity; chemicals; 21st-century; substitution; persistence; activation; mechanism

摘要

Chemical pollution is a global threat to human health, yet the toxicity mechanisms of most contaminants remains unknown. Here, we applied an ultrahigh-throughput affinity selection-mass spectrometry (AS-MS) platform to systematically identify protein targets of prioritized chemical contaminants. After benchmarking the platform, we screened 50 human proteins against 481 prioritized chemicals, including 446 ToxCast chemicals and 35 per- and polyfluoroalkyl substances (PFAS). Among 24,050 interactions assessed, we discovered 35 interactions involving 13 proteins, with fatty acid-binding proteins (FABPs) emerging as the most ligandable protein family. Given this, we selected FABPs for further validation, which revealed a distinct PFAS binding pattern: legacy PFAS selectively bound to FABP1, whereas replacement compounds, perfluoroether carboxylic acids, unexpectedly interacted with all FABPs. X-ray crystallography further revealed that the ether group enhances the molecular flexibility of alternative PFAS to accommodate the binding pockets of FABPs. Our findings demonstrate that AS-MS is a robust platform for the discovery of protein targets beyond the scope of ToxCast and highlight the broader protein-binding spectrum of alternative PFAS as potential regrettable substitutes.