TY  - JOUR
AU  - Sappington, Isaac
AU  - Toul, Martin
AU  - Lee, David S.
AU  - Robinson, Stephanie A.
AU  - Goreshnik, Inna
AU  - McCurdy, Clara
AU  - Chan, Tung Ching
AU  - Buchholz, Nic
AU  - Huang, Buwei
AU  - Vafeados, Dionne
AU  - Garcia-Sanchez, Mariana
AU  - Roullier, Nicole
AU  - Glögl, Matthias
AU  - Kim, Christopher J.
AU  - Watson, Joseph L.
AU  - Torres, Susana Vázquez
AU  - Verschueren, Koen H. G.
AU  - Verstraete, Kenneth
AU  - Hinck, Cynthia S.
AU  - Benard-Valle, Melisa
AU  - Coventry, Brian
AU  - Sims, Jeremiah Nelson
AU  - Ahn, Green
AU  - Wang, Xinru
AU  - Hinck, Andrew P.
AU  - Jenkins, Timothy P.
AU  - Ruohola-Baker, Hannele
AU  - Banik, Steven M.
AU  - Savvides, Savvas N.
AU  - Baker, David
TI  - Improved protein binder design using β-pairing targeted RFdiffusion
JO  - Nature Communications
VL  - 17
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - PUBDB-2026-00766
SP  - 1101
PY  - 2026
AB  - Designing proteins that bind with high affinity to hydrophilic protein target sites remains a challenging problem. Here we show that RFdiffusion can be conditioned to generate protein scaffolds that form geometrically matched extended β-sheets with target protein edge β-strands in which polar groups on the target are complemented with hydrogen bonding groups on the design. We use this approach to design binders against edge-strand target sites on KIT, PDGFRɑ, ALK-2, ALK-3, FCRL5, NRP1, and α-CTX, and obtain higher (pM to mid nM) affinities and success rates than unconditioned RFdiffusion. Despite sharing β-strand interactions, designs have high specificity, reflecting the precise customization of interacting β-strand geometry and additional designed binder-target interactions. A binder-KIT co-crystal structure is nearly identical to the design model, confirming the accuracy of the design approach. The ability to robustly generate binders to the hydrophilic interaction surfaces of exposed β-strands considerably increases the range of computational binder design.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1038/s41467-025-67866-3
UR  - https://bib-pubdb1.desy.de/record/646221
ER  -