6ZFM

Structure of alpha-Cobratoxin with a peptide inhibitor

Summary for 6ZFM

• Entry DOI: 10.2210/pdb6zfm/pdb
• Descriptor: Alpha-cobratoxin, peptide 12, 3-[2-[2-[2-[2-[2-(2-azanylethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propan-1-ol, ... (5 entities in total)
• Functional Keywords: cobratoxin, inhibitor, three-finger toxin, toxin
• Biological source: Naja kaouthia (Monocled cobra); More
• Total number of polymer chains: 6
• Total formula weight: 34588.13

Authors

Kiontke, S.,Kummel, D. (deposition date: 2020-06-17, release date: 2020-12-02, Last modification date: 2024-11-06)

Primary citation

Lynagh, T.,Kiontke, S.,Meyhoff-Madsen, M.,Gless, B.H.,Johannesen, J.,Kattelmann, S.,Christiansen, A.,Dufva, M.,Laustsen, A.H.,Devkota, K.,Olsen, C.A.,Kummel, D.,Pless, S.A.,Lohse, B.
Peptide Inhibitors of the alpha-Cobratoxin-Nicotinic Acetylcholine Receptor Interaction.
J.Med.Chem., 63:13709-13718, 2020

PubMed Abstract: Venomous snakebites cause >100 000 deaths every year, in many cases via potent depression of human neuromuscular signaling by snake α-neurotoxins. Emergency therapy still relies on antibody-based antivenom, hampered by poor access, frequent adverse reactions, and cumbersome production/purification. Combining high-throughput discovery and subsequent structure-function characterization, we present simple peptides that bind α-cobratoxin (α-Cbtx) and prevent its inhibition of nicotinic acetylcholine receptors (nAChRs) as a lead for the development of alternative antivenoms. Candidate peptides were identified by phage display and deep sequencing, and hits were characterized by electrophysiological recordings, leading to an 8-mer peptide that prevented α-Cbtx inhibition of nAChRs. We also solved the peptide:α-Cbtx cocrystal structure, revealing that the peptide, although of unique primary sequence, binds to α-Cbtx by mimicking structural features of the nAChR binding pocket. This demonstrates the potential of small peptides to neutralize lethal snake toxins in vitro, establishing a potential route to simple, synthetic, low-cost antivenoms.

PubMed: 33143415
DOI: 10.1021/acs.jmedchem.0c01202

Experimental method

X-RAY DIFFRACTION (1.9 Å)