3HH7

Structural and Functional Characterization of a Novel Homodimeric Three-finger Neurotoxin from the Venom of Ophiophagus hannah (King Cobra)

Summary for 3HH7

• Entry DOI: 10.2210/pdb3hh7/pdb
• Descriptor: Muscarinic toxin-like protein 3 homolog (2 entities in total)
• Functional Keywords: haditoxin, three finger toxin, ophiophagus hannah, snake venom, neurotoxin, nicotinic acetylcholine receptors, acetylcholine receptor inhibitor, disulfide bond, postsynaptic neurotoxin, secreted, toxin
• Biological source: Ophiophagus hannah (King cobra)
• Cellular location: Secreted : A8N286
• Total number of polymer chains: 2
• Total formula weight: 15104.88

Authors

Roy, A.,Zhou, X.,Chong, M.Z.,D'hoedt, D.,Foo, C.S.,Rajagopalan, N.,Nirthanan, S.,Bertrand, D.,Sivaraman, J.,Kini, R.M. (deposition date: 2009-05-15, release date: 2010-01-12, Last modification date: 2024-10-30)

Primary citation

Roy, A.,Zhou, X.,Chong, M.Z.,D'hoedt, D.,Foo, C.S.,Rajagopalan, N.,Nirthanan, S.,Bertrand, D.,Sivaraman, J.,Kini, R.M.
Structural and Functional Characterization of a Novel Homodimeric Three-finger Neurotoxin from the Venom of Ophiophagus hannah (King Cobra)
J.Biol.Chem., 285:8302-8315, 2010

PubMed Abstract: Snake venoms are a mixture of pharmacologically active proteins and polypeptides that have led to the development of molecular probes and therapeutic agents. Here, we describe the structural and functional characterization of a novel neurotoxin, haditoxin, from the venom of Ophiophagus hannah (King cobra). Haditoxin exhibited novel pharmacology with antagonism toward muscle (alphabetagammadelta) and neuronal (alpha(7), alpha(3)beta(2), and alpha(4)beta(2)) nicotinic acetylcholine receptors (nAChRs) with highest affinity for alpha(7)-nAChRs. The high resolution (1.5 A) crystal structure revealed haditoxin to be a homodimer, like kappa-neurotoxins, which target neuronal alpha(3)beta(2)- and alpha(4)beta(2)-nAChRs. Interestingly however, the monomeric subunits of haditoxin were composed of a three-finger protein fold typical of curaremimetic short-chain alpha-neurotoxins. Biochemical studies confirmed that it existed as a non-covalent dimer species in solution. Its structural similarity to short-chain alpha-neurotoxins and kappa-neurotoxins notwithstanding, haditoxin exhibited unique blockade of alpha(7)-nAChRs (IC(50) 180 nm), which is recognized by neither short-chain alpha-neurotoxins nor kappa-neurotoxins. This is the first report of a dimeric short-chain alpha-neurotoxin interacting with neuronal alpha(7)-nAChRs as well as the first homodimeric three-finger toxin to interact with muscle nAChRs.

PubMed: 20071329
DOI: 10.1074/jbc.M109.074161

Experimental method

X-RAY DIFFRACTION (1.55 Å)