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-Structure paper
| Title | De novo design of protein minibinder agonists of TLR3. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 16, Issue 1, Page 1234, Year 2025 |
| Publish date | Jan 31, 2025 |
 Authors | Chloe S Adams / Hyojin Kim / Abigail E Burtner / Dong Sun Lee / Craig Dobbins / Cameron Criswell / Brian Coventry / Adri Tran-Pearson / Ho Min Kim / Neil P King /   |
| PubMed Abstract | Toll-like Receptor 3 (TLR3) is a pattern recognition receptor that initiates antiviral immune responses upon binding double-stranded RNA (dsRNA). Several nucleic acid-based TLR3 agonists have been ...Toll-like Receptor 3 (TLR3) is a pattern recognition receptor that initiates antiviral immune responses upon binding double-stranded RNA (dsRNA). Several nucleic acid-based TLR3 agonists have been explored clinically as vaccine adjuvants in cancer and infectious disease, but present substantial manufacturing and formulation challenges. Here, we use computational protein design to create novel miniproteins that bind to human TLR3 with nanomolar affinities. Cryo-EM structures of two minibinders in complex with TLR3 reveal that they bind the target as designed, although one partially unfolds due to steric competition with a nearby N-linked glycan. Multivalent forms of both minibinders induce NF-κB signaling in TLR3-expressing cell lines, demonstrating that they may have therapeutically relevant biological activity. Our work provides a foundation for the development of specific, stable, and easy-to-formulate protein-based agonists of TLRs and other pattern recognition receptors. |
 External links | Nat Commun / PubMed:39890776 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.88 Å |
| Structure data | EMDB-39300, PDB-8yht: EMDB-39301, PDB-8yhu: |
| Chemicals |  ChemComp-NAG: |
| Source |
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 Keywords | DE NOVO PROTEIN / Protein design / binder / Innate immune / TLR |
homo sapiens (human)