Structural and Functional Characterization of a Novel Homodimeric Three-finger Neurotoxin from the Venom of Ophiophagus hannah (King Cobra)
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Snake venoms are a mixture of pharmacologically active proteins and polypeptides that have led to the development of 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 (a߿d) and neuronal (a7, a3߲, and a4߲) nicotinic acetylcholine receptors (nAChRs) with highest affinity for a7-nAChRs. The high resolution (1.5 ũ crystal structure revealed haditoxin to be a homodimer, like ?-neurotoxins, which target neuronal a3߲- and a4߲-nAChRs. Interestingly however, the monomeric subunits of haditoxin were composed of a three-finger protein fold typical of curaremimetic short-chain a-neurotoxins. Biochemical studies confirmed that it existed as a non-covalent dimer species in solution. Its structural similarity to short-chain a-neurotoxins and ?-neurotoxins notwithstanding, haditoxin exhibited unique blockade of a7-nAChRs (IC50 180 nm), which is recognized by neither short-chain a-neurotoxins nor ?-neurotoxins. This is the first report of a dimeric short-chain a-neurotoxin interacting with neuronal a7-nAChRs as well as the first homodimeric three-finger toxin to interact with muscle nAChRs.
Journal of Biological Chemistry
This research was originally published in Journal of Biological Chemistry (JBC). Authors, Structural and Functional Characterization of a Novel Homodimeric Three-finger Neurotoxin from the Venom of Ophiophagus hannah (King Cobra), Journal of Biological Chemistry (JBC) 2010; Vol 285: 8302-8315. Copyright the American Society for Biochemistry and Molecular Biology. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitve version.
Pharmacology and Pharmaceutical Sciences not elsewhere classified