Diffusing protein binders to intrinsically disordered proteins

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

Nature, 2025, vol. 644, issue 8077, 809-817

Abstract: 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 applications1–4. 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 100 nM. 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 100 nM. 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.

Date: 2025
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DOI: 10.1038/s41586-025-09248-9

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