9CC6

De novo design of high-affinity protein binders to RNA binding domain of G3bp1

9CC6 の概要

• エントリーDOI: 10.2210/pdb9cc6/pdb
• 分子名称: G3bp1 Binder, Ras GTPase-activating protein-binding protein 1 (3 entities in total)
• 機能のキーワード: protein design, diffusion, deep learning, de novo protein, binders, idp, idr, phase separation
• 由来する生物種: synthetic construct; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 18632.28

構造登録者

Bera, A.K.,Liu, C.,Kang, A.,Baker, D. (登録日: 2024-06-20, 公開日: 2025-05-14, 最終更新日: 2025-08-27)

主引用文献

Liu, C.,Wu, K.,Choi, H.,Han, H.L.,Zhang, X.,Watson, J.L.,Ahn, G.,Zhang, J.Z.,Shijo, S.,Good, L.L.,Fischer, C.M.,Bera, A.K.,Kang, A.,Brackenbrough, E.,Coventry, B.,Hick, D.R.,Qamar, S.,Li, X.,Decarreau, J.,Gerben, S.R.,Yang, W.,Goreshnik, I.,Vafeados, D.,Wang, X.,Lamb, M.,Murray, A.,Kenny, S.,Bauer, M.S.,Hoofnagle, A.N.,Zhu, P.,Knowles, T.P.J.,Baker, D.
Diffusing protein binders to intrinsically disordered proteins.
Nature, 644:809-817, 2025

PubMed 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 applications. 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, RFdiffusion 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 (K) 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 K 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.

PubMed: 40739343
DOI: 10.1038/s41586-025-09248-9

実験手法

X-RAY DIFFRACTION (2.4 Å)