Wu Kejia, Jiang Hanlun, Hicks Derrick R, Liu Caixuan, Muratspahić 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
Department of Biochemistry, University of Washington, Seattle, WA, USA.
Institute for Protein Design, University of Washington, Seattle, WA, USA.
Science. 2025 Jul 17;389(6757):eadr8063. doi: 10.1126/science.adr8063.
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 ~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.
内在无序蛋白和肽在生物学中发挥着关键作用，但缺乏明确的结构以及序列和构象偏好的高度变异性使得靶向这类系统具有挑战性。我们描述了一种通用方法，用于设计能够结合处于不同延伸构象的内在无序蛋白区域的蛋白质，其侧链可适配互补结合口袋。我们运用该方法为39个高度多样化的非结构化靶标设计结合剂，包括极性靶标，在34个案例中获得了亲和力为100皮摩尔至100纳摩尔的设计，每个靶标测试约22种设计。这些设计在细胞中发挥作用并作为检测试剂，在全对全结合实验中对其预期靶标具有特异性。我们的方法是朝着全面解决内在无序蛋白和肽识别问题迈出的重要一步。
