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@ARTICLE{Sappington:646221,
author = {Sappington, Isaac and Toul, Martin and Lee, David S. and
Robinson, Stephanie A. and Goreshnik, Inna and McCurdy,
Clara and Chan, Tung Ching and Buchholz, Nic and Huang,
Buwei and Vafeados, Dionne and Garcia-Sanchez, Mariana and
Roullier, Nicole and Glögl, Matthias and Kim, Christopher
J. and Watson, Joseph L. and Torres, Susana Vázquez and
Verschueren, Koen H. G. and Verstraete, Kenneth and Hinck,
Cynthia S. and Benard-Valle, Melisa and Coventry, Brian and
Sims, Jeremiah Nelson and Ahn, Green and Wang, Xinru and
Hinck, Andrew P. and Jenkins, Timothy P. and Ruohola-Baker,
Hannele and Banik, Steven M. and Savvides, Savvas N. and
Baker, David},
title = {{I}mproved protein binder design using β-pairing targeted
{RF}diffusion},
journal = {Nature Communications},
volume = {17},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Springer Nature},
reportid = {PUBDB-2026-00766},
pages = {1101},
year = {2026},
abstract = {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.},
cin = {EMBL-User},
ddc = {500},
cid = {I:(DE-H253)EMBL-User-20120814},
pnm = {6G3 - PETRA III (DESY) (POF4-6G3)},
pid = {G:(DE-HGF)POF4-6G3},
experiment = {EXP:(DE-H253)P-P13-20150101},
typ = {PUB:(DE-HGF)16},
doi = {10.1038/s41467-025-67866-3},
url = {https://bib-pubdb1.desy.de/record/646221},
}