华盛顿大学David Baker小组取得一项新突破。他们的研究显示，扩散性蛋白结合剂与固有无序蛋白的结合。这一研究成果于2025年7月30日发表在国际顶尖学术期刊《自然》上。

在这里，该课题组展示了仅从输入的目标序列开始，并自由采样目标和结合蛋白构象，RFdiffthemion5可以生成广泛构象的IDPs和IDRs的结合物。研究小组利用这种方法制备了不同构象的IDPs amylin、C-peptide、VP48和BRCA1_ARATH的结合物，其解离常数（K_d）在3-100nm之间。对于IDRs G3BP1，常见的细胞因子受体γ链（IL-2RG）和朊病毒蛋白，该课题组人员根据靶标的β-链构象对结合物进行了差异化，得到了10-100nm之间的K_d。荧光成像实验表明，这些结合剂与细胞中各自的靶标结合。G3BP1结合剂破坏细胞中应激颗粒的形成，而胰淀素结合剂抑制淀粉样纤维的形成并解离现有纤维，使溶酶体能够靶向单体和纤维状胰淀素，并提高基于质谱的胰淀素检测的灵敏度。他们的方法应该是为灵活的IDPs和IDRs创造粘合剂的主题，这些粘合剂跨越了广泛的内在构象偏好。

据介绍，具有高亲和力和特异性结合内在无序蛋白（IDPs）和内在无序区（IDRs）的蛋白质可能是治疗和诊断应用的主题。然而，针对国内流离失所者或境内流离失所者的一般方法尚未制订。

附：英文原文

Title: Diffusing protein binders to intrinsically disordered proteins

Author: Liu, Caixuan, Wu, Kejia, Choi, Hojun, Han, Hannah L., Zhang, Xueli, Watson, Joseph L., Ahn, Green, Zhang, Jason Z., Shijo, Sara, Good, Lydia L., Fischer, Charlotte M., Bera, Asim K., Kang, Alex, Brackenbrough, Evans, Coventry, Brian, Hick, Derrick R., Qamar, Seema, Li, Xinting, Decarreau, Justin, Gerben, Stacey R., Yang, Wei, Goreshnik, Inna, Vafeados, Dionne, Wang, Xinru, Lamb, Mila, Murray, Analisa, Kenny, Sebastian, Bauer, Magnus S., Hoofnagle, Andrew N., Zhu, Ping, Knowles, Tuomas P. J., Baker, David

Issue&Volume: 2025-07-30

Abstract: Proteins that bind to intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) with high affinity and specificity could be useful for therapeutic and diagnostic applications1,2,3,4. However, a general methodology for targeting IDPs or IDRs has yet to be developed. Here we show that starting only from the target sequence of the input, and freely sampling both target and binding protein conformations, RFdiffusion5 can generate binders to IDPs and IDRs in a wide range of conformations. We used this approach to generate binders to the IDPs amylin, C-peptide, VP48 and BRCA1_ARATH in diverse conformations with a dissociation constant (Kd) ranging from 3 to 100nM. For the IDRs G3BP1, common cytokine receptor γ-chain (IL-2RG) and prion protein, we diffused binders to β-strand conformations of the targets, obtaining Kd between 10 and 100nM. Fluorescence imaging experiments show that the binders bind to their respective targets in cells. The G3BP1 binder disrupts stress granule formation in cells, and the amylin binder inhibits amyloid fibril formation and dissociates existing fibres, enables targeting of both monomeric and fibrillar amylin to lysosomes, and increases the sensitivity of mass spectrometry-based amylin detection. Our approach should be useful for creating binders to flexible IDPs or IDRs spanning a wide range of intrinsic conformational preferences.

DOI: 10.1038/s41586-025-09248-9

Source: https://www.nature.com/articles/s41586-025-09248-9