9BK5

Structure of LNG binder complex

Summary for 9BK5

• Entry DOI: 10.2210/pdb9bk5/pdb
• Descriptor: LNG binder, Alpha-cobratoxin (2 entities in total)
• Functional Keywords: cobra toxin, protein design, diffusion, deep learning, de novo protein, de novo protein-toxin complex, de novo protein/toxin
• Biological source: synthetic construct; More
• Total number of polymer chains: 2
• Total formula weight: 20780.48

Authors

Bera, A.K.,Torres, S.V.,Kang, A.,Baker, D. (deposition date: 2024-04-26, release date: 2024-10-09, Last modification date: 2025-03-12)

Primary citation

Vazquez Torres, S.,Benard Valle, M.,Mackessy, S.P.,Menzies, S.K.,Casewell, N.R.,Ahmadi, S.,Burlet, N.J.,Muratspahic, E.,Sappington, I.,Overath, M.D.,Rivera-de-Torre, E.,Ledergerber, J.,Laustsen, A.H.,Boddum, K.,Bera, A.K.,Kang, A.,Brackenbrough, E.,Cardoso, I.A.,Crittenden, E.P.,Edge, R.J.,Decarreau, J.,Ragotte, R.J.,Pillai, A.S.,Abedi, M.,Han, H.L.,Gerben, S.R.,Murray, A.,Skotheim, R.,Stuart, L.,Stewart, L.,Fryer, T.J.A.,Jenkins, T.P.,Baker, D.
De novo designed proteins neutralize lethal snake venom toxins.
Nature, 639:225-231, 2025

PubMed Abstract: Snakebite envenoming remains a devastating and neglected tropical disease, claiming over 100,000 lives annually and causing severe complications and long-lasting disabilities for many more. Three-finger toxins (3FTx) are highly toxic components of elapid snake venoms that can cause diverse pathologies, including severe tissue damage and inhibition of nicotinic acetylcholine receptors, resulting in life-threatening neurotoxicity. At present, the only available treatments for snakebites consist of polyclonal antibodies derived from the plasma of immunized animals, which have high cost and limited efficacy against 3FTxs. Here we used deep learning methods to de novo design proteins to bind short-chain and long-chain α-neurotoxins and cytotoxins from the 3FTx family. With limited experimental screening, we obtained protein designs with remarkable thermal stability, high binding affinity and near-atomic-level agreement with the computational models. The designed proteins effectively neutralized all three 3FTx subfamilies in vitro and protected mice from a lethal neurotoxin challenge. Such potent, stable and readily manufacturable toxin-neutralizing proteins could provide the basis for safer, cost-effective and widely accessible next-generation antivenom therapeutics. Beyond snakebite, our results highlight how computational design could help democratize therapeutic discovery, particularly in resource-limited settings, by substantially reducing costs and resource requirements for the development of therapies for neglected tropical diseases.

PubMed: 39814879
DOI: 10.1038/s41586-024-08393-x

Experimental method

X-RAY DIFFRACTION (2.68 Å)