9HAC

De novo designed BBF-14 beta barrel with computationally designed BBF-14_b4 binder

Summary for 9HAC

• Entry DOI: 10.2210/pdb9hac/pdb
• Descriptor: BBF-14, BBF-14_binder4, HEXAETHYLENE GLYCOL, ... (7 entities in total)
• Functional Keywords: beta barrel, bbf-14, computational, binder, de novo protein
• Biological source: synthetic construct; More
• Total number of polymer chains: 4
• Total formula weight: 63450.44

Authors

Pacesa, M.,Nickel, L.,Correia, B.E. (deposition date: 2024-11-03, release date: 2024-12-18, Last modification date: 2025-09-03)

Primary citation

Pacesa, M.,Nickel, L.,Schellhaas, C.,Schmidt, J.,Pyatova, E.,Kissling, L.,Barendse, P.,Choudhury, J.,Kapoor, S.,Alcaraz-Serna, A.,Cho, Y.,Ghamary, K.H.,Vinue, L.,Yachnin, B.J.,Wollacott, A.M.,Buckley, S.,Westphal, A.H.,Lindhoud, S.,Georgeon, S.,Goverde, C.A.,Hatzopoulos, G.N.,Gonczy, P.,Muller, Y.D.,Schwank, G.,Swarts, D.C.,Vecchio, A.J.,Schneider, B.L.,Ovchinnikov, S.,Correia, B.E.
One-shot design of functional protein binders with BindCraft.
Nature, 2025

PubMed Abstract: Protein-protein interactions are at the core of all key biological processes. However, the complexity of the structural features that determine protein-protein interactions makes their design challenging. Here we present BindCraft, an open-source and automated pipeline for de novo protein binder design with experimental success rates of 10-100%. BindCraft leverages the weights of AlphaFold2 (ref. ) to generate binders with nanomolar affinity without the need for high-throughput screening or experimental optimization, even in the absence of known binding sites. We successfully designed binders against a diverse set of challenging targets, including cell-surface receptors, common allergens, de novo designed proteins and multi-domain nucleases, such as CRISPR-Cas9. We showcase the functional and therapeutic potential of designed binders by reducing IgE binding to birch allergen in patient-derived samples, modulating Cas9 gene editing activity and reducing the cytotoxicity of a foodborne bacterial enterotoxin. Last, we use cell-surface-receptor-specific binders to redirect adeno-associated virus capsids for targeted gene delivery. This work represents a significant advancement towards a 'one design-one binder' approach in computational design, with immense potential in therapeutics, diagnostics and biotechnology.

PubMed: 40866699
DOI: 10.1038/s41586-025-09429-6

Experimental method

X-RAY DIFFRACTION (3.1 Å)