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J Biol Chem
2010 Mar 12;28511:8302-15. doi: 10.1074/jbc.M109.074161.
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Structural and functional characterization of a novel homodimeric three-finger neurotoxin from the venom of Ophiophagus hannah (king cobra).
Roy A, Zhou X, Chong MZ, D'hoedt D, Foo CS, Rajagopalan N, Nirthanan S, Bertrand D, Sivaraman J, Kini RM.
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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.
Aird,
Primary structure of gamma-bungarotoxin, a new postsynaptic neurotoxin from venom of Bungarus multicinctus.
1999, Pubmed
Aird,
Primary structure of gamma-bungarotoxin, a new postsynaptic neurotoxin from venom of Bungarus multicinctus.
1999,
Pubmed Antil,
Variability among the sites by which curaremimetic toxins bind to torpedo acetylcholine receptor, as revealed by identification of the functional residues of alpha-cobratoxin.
1999,
Pubmed Antil-Delbeke,
Molecular determinants by which a long chain toxin from snake venom interacts with the neuronal alpha 7-nicotinic acetylcholine receptor.
2000,
Pubmed Barlow,
Coevolution of diet and prey-specific venom activity supports the role of selection in snake venom evolution.
2009,
Pubmed Berman,
The Protein Data Bank.
2000,
Pubmed Bourne,
Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors.
2005,
Pubmed Bülbring,
Observations on the isolated phrenic nerve diaphragm preparation of the rat. 1946.
1997,
Pubmed Changeux,
Use of a snake venom toxin to characterize the cholinergic receptor protein.
1970,
Pubmed Changeux,
The TiPS lecture. The nicotinic acetylcholine receptor: an allosteric protein prototype of ligand-gated ion channels.
1990,
Pubmed Chiappinelli,
Kappa-neurotoxins: heterodimer formation between different neuronal nicotinic receptor antagonists.
1989,
Pubmed Chiappinelli,
kappa-Bungarotoxin. Self-association of a neuronal nicotinic receptor probe.
1985,
Pubmed Colquhoun,
Pharmacology of neuronal nicotinic acetylcholine receptor subtypes.
1997,
Pubmed Coulson,
Insulin regulates neuronal M2 muscarinic receptor function in the ileum of diabetic rats.
2004,
Pubmed Daltry,
Diet and snake venom evolution.
1996,
Pubmed Dellisanti,
Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution.
2007,
Pubmed Dewan,
Crystal structure of kappa-bungarotoxin at 2.3-A resolution.
1994,
Pubmed de Weille,
Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel.
1991,
Pubmed Emsley,
Coot: model-building tools for molecular graphics.
2004,
Pubmed Fiordalisi,
Site-directed mutagenesis of kappa-bungarotoxin: implications for neuronal receptor specificity.
1994,
Pubmed Fruchart-Gaillard,
Experimentally based model of a complex between a snake toxin and the alpha 7 nicotinic receptor.
2002,
Pubmed Gille,
STRAP: editor for STRuctural Alignments of Proteins.
2001,
Pubmed GINSBORG,
The isolated chick biventer cervicis nerve-muscle preparation.
1960,
Pubmed Gouet,
ESPript: analysis of multiple sequence alignments in PostScript.
1999,
Pubmed Grant,
kappa-Bungarotoxin: complete amino acid sequence of a neuronal nicotinic receptor probe.
1985,
Pubmed Grant,
Differential roles for disulfide bonds in the structural integrity and biological activity of kappa-Bungarotoxin, a neuronal nicotinic acetylcholine receptor antagonist.
1998,
Pubmed
,
Xenbase Grant,
Critical interactions at the dimer interface of kappa-bungarotoxin, a neuronal nicotinic acetylcholine receptor antagonist.
1997,
Pubmed Grutter,
Nicotinic receptors in wonderland.
2001,
Pubmed Harvey,
Effects of muscarinic toxins MT1 and MT2 from green mamba on different muscarinic cholinoceptors.
2002,
Pubmed Harvey,
Toxins 'R' Us: more pharmacological tools from nature's superstore.
2002,
Pubmed Herz,
Distance between the agonist and noncompetitive inhibitor sites on the nicotinic acetylcholine receptor.
1989,
Pubmed Hogg,
An automated system for intracellular and intranuclear injection.
2008,
Pubmed
,
Xenbase Jiang,
Isolation and pharmacological characterization of a new alpha-neurotoxin (alpha-AgTx) from venom of the viper Agkistrodon halys (Pallas).
1987,
Pubmed KATZ,
A study of the desensitization produced by acetylcholine at the motor end-plate.
1957,
Pubmed Kini,
Molecular moulds with multiple missions: functional sites in three-finger toxins.
2002,
Pubmed Krissinel,
Inference of macromolecular assemblies from crystalline state.
2007,
Pubmed Kumar,
Snake venom cardiotoxins-structure, dynamics, function and folding.
1997,
Pubmed Kuruppu,
Isolation and pharmacological characterisation of papuantoxin-1, a postsynaptic neurotoxin from the venom of the Papuan black snake (Pseudechis papuanus).
2005,
Pubmed Langley,
On the contraction of muscle, chiefly in relation to the presence of "receptive" substances: Part I.
1907,
Pubmed Laothong,
Decreased parasympathetic activities in Malayan krait (Bungarus candidus) envenoming.
2001,
Pubmed Lewis,
Therapeutic potential of venom peptides.
2003,
Pubmed Lumsden,
Pharmacological characterisation of a neurotoxin from the venom of Boiga dendrophila (mangrove catsnake).
2005,
Pubmed Mackessy,
Venom of the Brown Treesnake, Boiga irregularis: ontogenetic shifts and taxa-specific toxicity.
2006,
Pubmed McDowell,
Mambin, a potent glycoprotein IIb-IIIa antagonist and platelet aggregation inhibitor structurally related to the short neurotoxins.
1992,
Pubmed Ménez,
Refolding of reduced short neurotoxins: circular dichroism analysis.
1980,
Pubmed Nirthanan,
Three-finger alpha-neurotoxins and the nicotinic acetylcholine receptor, forty years on.
2004,
Pubmed Nirthanan,
Neuromuscular effects of candoxin, a novel toxin from the venom of the Malayan krait (Bungarus candidus).
2003,
Pubmed Nirthanan,
Candoxin, a novel toxin from Bungarus candidus, is a reversible antagonist of muscle (alphabetagammadelta ) but a poorly reversible antagonist of neuronal alpha 7 nicotinic acetylcholine receptors.
2002,
Pubmed Ohno,
Molecular evolution of snake toxins: is the functional diversity of snake toxins associated with a mechanism of accelerated evolution?
1998,
Pubmed Olianas,
Selectivity profile of muscarinic toxin 3 in functional assays of cloned and native receptors.
1999,
Pubmed Osipov,
Naturally occurring disulfide-bound dimers of three-fingered toxins: a paradigm for biological activity diversification.
2008,
Pubmed
,
Xenbase Oswald,
Solution structure of neuronal bungarotoxin determined by two-dimensional NMR spectroscopy: sequence-specific assignments, secondary structure, and dimer formation.
1991,
Pubmed Otwinowski,
Processing of X-ray diffraction data collected in oscillation mode.
1997,
Pubmed Pahari,
The venom gland transcriptome of the Desert Massasauga rattlesnake (Sistrurus catenatus edwardsii): towards an understanding of venom composition among advanced snakes (Superfamily Colubroidea).
2007,
Pubmed Pahari,
Expression pattern of three-finger toxin and phospholipase A2 genes in the venom glands of two sea snakes, Lapemis curtus and Acalyptophis peronii: comparison of evolution of these toxins in land snakes, sea kraits and sea snakes.
2007,
Pubmed Palma,
Neuronal nicotinic alpha 7 receptor expressed in Xenopus oocytes presents five putative binding sites for methyllycaconitine.
1996,
Pubmed
,
Xenbase Pawlak,
Denmotoxin, a three-finger toxin from the colubrid snake Boiga dendrophila (Mangrove Catsnake) with bird-specific activity.
2006,
Pubmed Pawlak,
Irditoxin, a novel covalently linked heterodimeric three-finger toxin with high taxon-specific neurotoxicity.
2009,
Pubmed Perrakis,
Automated protein model building combined with iterative structure refinement.
1999,
Pubmed Pung,
Ohanin, a novel protein from king cobra venom, induces hypolocomotion and hyperalgesia in mice.
2005,
Pubmed Rajagopalan,
Beta-cardiotoxin: a new three-finger toxin from Ophiophagus hannah (king cobra) venom with beta-blocker activity.
2007,
Pubmed Ricciardi,
Do structural deviations between toxins adopting the same fold reflect functional differences?
2000,
Pubmed Servent,
Molecular characterization of the specificity of interactions of various neurotoxins on two distinct nicotinic acetylcholine receptors.
2000,
Pubmed Servent,
Muscarinic toxins: tools for the study of the pharmacological and functional properties of muscarinic receptors.
2009,
Pubmed Servent,
How do snake curaremimetic toxins discriminate between nicotinic acetylcholine receptor subtypes.
1998,
Pubmed Starkov,
[New weak toxins from the cobra venom].
2009,
Pubmed Staros,
N-hydroxysulfosuccinimide active esters: bis(N-hydroxysulfosuccinimide) esters of two dicarboxylic acids are hydrophilic, membrane-impermeant, protein cross-linkers.
1982,
Pubmed Tan,
Isolation and pharmacological characterisation of hostoxin-1, a postsynaptic neurotoxin from the venom of the Stephen's banded snake (Hoplocephalus stephensi).
2006,
Pubmed Teixeira-Clerc,
How do short neurotoxins bind to a muscular-type nicotinic acetylcholine receptor?
2002,
Pubmed Torres,
NMR structure of bucandin, a neurotoxin from the venom of the Malayan krait (Bungarus candidus).
2001,
Pubmed Trémeau,
Genetic engineering of snake toxins. The functional site of Erabutoxin a, as delineated by site-directed mutagenesis, includes variant residues.
1995,
Pubmed Tsetlin,
Snake venom alpha-neurotoxins and other 'three-finger' proteins.
1999,
Pubmed Unwin,
Nicotinic acetylcholine receptor at 9 A resolution.
1993,
Pubmed Vagin,
REFMAC5 dictionary: organization of prior chemical knowledge and guidelines for its use.
2004,
Pubmed Warrell,
Severe neurotoxic envenoming by the Malayan krait Bungarus candidus (Linnaeus): response to antivenom and anticholinesterase.
1983,
Pubmed Weiser,
Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle.
1997,
Pubmed Wolf,
kappa-Bungarotoxin: binding of a neuronal nicotinic receptor antagonist to chick optic lobe and skeletal muscle.
1988,
Pubmed
