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: 2024-12-25)

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.
BindCraft: one-shot design of functional protein binders.
Biorxiv, 2024

PubMed Abstract: Protein-protein interactions (PPIs) are at the core of all key biological processes. However, the complexity of the structural features that determine PPIs makes their design challenging. We present BindCraft, an open-source and automated pipeline for protein binder design with experimental success rates of 10-100%. BindCraft leverages the weights of AlphaFold2 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, 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. Lastly, we utilize cell surface receptor-specific binders to redirect AAV 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: 39677777
DOI: 10.1101/2024.09.30.615802

Experimental method

X-RAY DIFFRACTION (3.1 Å)