8G4K

Complex of TbRII mini protein binder bound to the TbRII ECD

Summary for 8G4K

• Entry DOI: 10.2210/pdb8g4k/pdb
• Descriptor: 5HCS_TGFBR2_1, TGF-beta receptor type-2, SULFATE ION, ... (4 entities in total)
• Functional Keywords: tbrii, tgf-b type ii receptor, computationally designed mini protein binder, mpb, signaling protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 2
• Total formula weight: 24360.07

Authors

Schwartze, T.S.,Hinck, A.P. (deposition date: 2023-02-09, release date: 2024-08-14, Last modification date: 2025-09-03)

Primary citation

Yang, W.,Hicks, D.R.,Ghosh, A.,Schwartze, T.A.,Conventry, B.,Goreshnik, I.,Allen, A.,Halabiya, S.F.,Kim, C.J.,Hinck, C.S.,Lee, D.S.,Bera, A.K.,Li, Z.,Wang, Y.,Schlichthaerle, T.,Cao, L.,Huang, B.,Garrett, S.,Gerben, S.R.,Rettie, S.,Heine, P.,Murray, A.,Edman, N.,Carter, L.,Stewart, L.,Almo, S.C.,Hinck, A.P.,Baker, D.
Design of high-affinity binders to immune modulating receptors for cancer immunotherapy.
Nat Commun, 16:2001-2001, 2025

PubMed Abstract: Immune receptors have emerged as critical therapeutic targets for cancer immunotherapy. Designed protein binders can have high affinity, modularity, and stability and hence could be attractive components of protein therapeutics directed against these receptors, but traditional Rosetta based protein binder methods using small globular scaffolds have difficulty achieving high affinity on convex targets. Here we describe the development of helical concave scaffolds tailored to the convex target sites typically involved in immune receptor interactions. We employed these scaffolds to design proteins that bind to TGFβRII, CTLA-4, and PD-L1, achieving low nanomolar to picomolar affinities and potent biological activity following experimental optimization. Co-crystal structures of the TGFβRII and CTLA-4 binders in complex with their respective receptors closely match the design models. These designs should have considerable utility for downstream therapeutic applications.

PubMed: 40011465
DOI: 10.1038/s41467-025-57192-z

Experimental method

X-RAY DIFFRACTION (1.24 Å)