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
bioRxiv. 2025 Feb 8:2024.07.15.603480. doi: 10.1101/2024.07.15.603480.
Intrinsically disordered proteins and peptides play key roles in biology, but the lack of defined structures and the high variability in sequence and conformational preferences has 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 and obtain designs with pM to 100 nM affinities in 34 cases, testing ∼22 designs per target (including polar targets). 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 towards a general solution to the intrinsically disordered protein and peptide recognition problem.
内在无序蛋白质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针对此类系统的研究具有挑战性。我们描述了一种设计蛋白质的通用方法，该方法可结合具有不同延伸构象的内在无序蛋白质区域，其侧链可适配到互补的结合口袋中。我们使用该方法为39个高度多样化的无结构靶标设计结合蛋白，并在34个案例中获得了亲和力在皮摩尔至100纳摩尔之间的设计，每个靶标测试约22种设计（包括极性靶标）。这些设计在细胞中发挥作用并作为检测试剂，并且在全对全结合实验中对其预期靶标具有特异性。我们的方法是朝着解决内在无序蛋白质和肽识别问题的通用解决方案迈出的重要一步。
