Design of intrinsically disordered region binding proteins

• 成果类型: Article
• 署名作者: Wu, Kejia; Jiang, Hanlun; Hicks, Derrick R.; Liu, Caixuan; Muratspahic, Edin; Ramelot, Theresa A.; Liu, Yuexuan; McNally, Kerrie; Kenny, Sebastian; Mihut, Andrei; Gaur, Amit; Coventry, Brian; Chen, Wei; Bera, Asim K.; Kang, Alex; Gerben, Stacey; Lamb, Mila Ya-Lan; Murray, Analisa; Li, Xinting; Kennedy, Madison A.; Yang, Wei; Song, Zihao; Schober, Gudrun; Brierley, Stuart M.; O'Neill, John; Gelb, Michael H.; Montelione, Gaetano T.; Derivery, Emmanuel; Baker, David
• 署名单位: University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; University of California System; University of California Berkeley; Rensselaer Polytechnic Institute; University of Washington; University of Washington Seattle; MRC Laboratory Molecular Biology; University of Washington; University of Washington Seattle; Howard Hughes Medical Institute; South Australian Health & Medical Research Institute (SAHMRI); University of Adelaide
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9108
• DOI: 10.1126/science.adr8063
• 发表日期: 2025-07-17
• 关键词: modular peptide-binding; kappa-opioid receptor; fusion protein; repeat; dynorphin; SYSTEM; server

摘要

Intrinsically disordered proteins and peptides play key roles in biology, but a lack of defined structures and high variability in sequence and conformational preferences have made targeting such systems challenging. We describe a general approach for designing proteins that bind intrinsically disordered protein regions in diverse extended conformations with side chains fitting into complementary binding pockets. We used the approach to design binders for 39 highly diverse unstructured targets, including polar targets, and obtained designs with 100-picomolar to 100-nanomolar affinities in 34 cases, testing similar to 22 designs per target. The designs function in cells and as detection reagents and are specific for their intended targets in all-by-all binding experiments. Our approach is a major step toward a general solution to the intrinsically disordered protein and peptide recognition problem.