Determination of three-dimensional solution structure of waglerin I, a toxin from Trimeresurus wagleri, using 2D-NMR and molecular dynamics simulation

Chuang, Li Chin; Yu, Hsiao-Wei; Chen, Chinpan; Huang, Tai Huang; Wu, Shih Hsiung; Wang, Kung Tsung

doi:10.1016/0167-4838(95)00181-6

Cited by 10 publications

(15 citation statements)

References 22 publications

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“…We suggest that azemiopsin may adopt a hairpin-like structure additionally stabilized by cation-π interactions between the N-terminal tryptophan residues and C-terminal arginine or lysine residues. Interestingly, the 1 H NMR study of synthetic waglerin I did not reveal any secondary structure in solution (30). However, the central region of waglerin I is well defined as a rigid disulfide-bonded loop, whereas its N and C termini are essentially disordered.…”

Section: Discussionmentioning

confidence: 99%

Azemiopsin from Azemiops feae Viper Venom, a Novel Polypeptide Ligand of Nicotinic Acetylcholine Receptor

Utkin

Weise

Kasheverov

et al. 2012

Journal of Biological Chemistry

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Background: Venoms from rare snake species may contain toxins of new structural or/and pharmacological types.Results: Amino acid sequence of the new polypeptide azemiopsin isolated from Azemiops feae viper venom was established, and its biological activity was determined.Conclusion: Azemiopsin is the first natural toxin that blocks nicotinic acetylcholine receptors and does not contain disulfide bridges.Significance: Azemiopsin is the first member of a new toxin group.

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Section: Discussionmentioning

confidence: 99%

Azemiopsin from Azemiops feae Viper Venom, a Novel Polypeptide Ligand of Nicotinic Acetylcholine Receptor

Utkin

Weise

Kasheverov

et al. 2012

Journal of Biological Chemistry

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“…Waglerins contain 22–24 residues, an unusually high proline content, and a single disulfide bond that forms a central loop with only three intervening residues. In solution, Waglerin-1 assumes the shape of the letter Y in which the two branches are flexible and their conformations depend on the polarity of the environment, potentially enabling the peptide to conform to the binding site (56, 230). Toxicity of Waglerin-1 depends on species, with mice very sensitive and rats insensitive (159).…”

Section: Pharmacologymentioning

confidence: 99%

End-Plate Acetylcholine Receptor: Structure, Mechanism, Pharmacology, and Disease

Sine

2012

Physiological Reviews

112

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The synapse is a localized neurohumoral contact between a neuron and an effector cell and may be considered the quantum of fast intercellular communication. Analogously, the postsynaptic neurotransmitter receptor may be considered the quantum of fast chemical to electrical transduction. Our understanding of postsynaptic receptors began to develop about a hundred years ago with the demonstration that electrical stimulation of the vagus nerve released acetylcholine and slowed the heart beat. During the past 50 years, advances in understanding postsynaptic receptors increased at a rapid pace, owing largely to studies of the acetylcholine receptor (AChR) at the motor endplate. The endplate AChR belongs to a large superfamily of neurotransmitter receptors, called Cys-loop receptors, and has served as an exemplar receptor for probing fundamental structures and mechanisms that underlie fast synaptic transmission in the central and peripheral nervous systems. Recent studies provide an increasingly detailed picture of the structure of the AChR and the symphony of molecular motions that underpin its remarkably fast and efficient chemoelectrical transduction.

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“…The solved NMR structures for Waglerin-1 (14,15) show there is a single intramolecular disulfide between the two cysteines.…”

mentioning

confidence: 99%

“…Wagler's pit viper, Tropidolaemus wagleri, is unique among Viperids for morphological reasons as well as for the unique components of its venom. Four related peptides, whose sequence differences are boldfaced, have been isolated from the venom of this species, all of which cause paralysis by neuromuscular blockade (9 -12) and are selective for the adult form of the receptor (13).The solved NMR structures for 15) show there is a single intramolecular disulfide between the two cysteines.The present work was inspired by observations of C. Y. Lee and colleagues who nearly forty years ago showed that ␣-bungarotoxin irreversibly blocks neuromuscular transmission (16). Their more recent studies indicate a remarkable difference in waglerin toxicity between mice and rats (17).…”

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confidence: 99%

Identification of Residues at the α and ε Subunit Interfaces Mediating Species Selectivity of Waglerin-1 for Nicotinic Acetylcholine Receptors

Molles¹,

Rezai²,

Kline³

et al. 2002

Journal of Biological Chemistry

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Waglerin-1 (Wtx-1) is a 22-amino acid peptide that is a competitive antagonist of the muscle nicotinic receptor (nAChR). We find that Wtx-1 binds 2100-fold more tightly to the ␣-⑀ than to the ␣-␦ binding site interface of the mouse nAChR. Moreover, Wtx-1 binds 100-fold more tightly to the ␣-⑀ interface from mouse nAChR than that from rat or human sources. Site-directed mutagenesis of residues differing in the extracellular domains of rat and mouse ⑀ subunits indicates that residues 59 and 115 mediate the species difference in Wtx-1 affinity. Mutation of residues 59 (Asp in mouse, Glu in rat ⑀) and 115 (Tyr in mouse, Ser in rat ⑀) converts Wtx-1 affinity for the ␣-⑀ interface of one species to that of the other species. Studies of different mutations at position 59 indicate both steric and electrostatic contributions to Wtx-1 affinity, whereas at position 115, both aromatic and polar groups contribute to affinity. The human nAChR also has lower affinity for Wtx-1 than mouse nAChR, but unlike rat nAChR, residues in both ␣ and ⑀ subunits mediate the affinity difference. In human nAChR, polar residues (Ser-187 and Thr-189) confer low affinity, whereas in mouse nAChR aromatic residues (Trp-187 and Phe-189) confer high affinity. The overall results show that non-conserved residues at the nAChR binding site, although not crucial for activation by ACh, govern the potency of neuromuscular toxins.The muscle nicotinic receptor (1-3) contains five polypeptide subunits arranged with radial symmetry around a central pore. Two copies of ␣ and one each of ␤, ␦, and ␥ (in the embryonic receptor form) or ⑀ (in the adult form) (4) are arranged around the central pore in the counterclockwise order: ␣-␥/⑀-␣-␦-␤ as established from the crystal structure determination of the acetylcholine binding protein from the freshwater snail Lymnaea stagnalis (5, 6). Each of the five subunits contains between 445 and 497 amino acids with residues 1 through ϳ210 forming the extracellular ligand binding domain. Each receptor subunit has up to three N-linked glycosylation sites and four transmembrane spans, giving the pentamer a molecular mass of nearly 300 kDa with 20 membrane spans. The binding sites for agonists and competitive antagonists are found at interfaces of the ␣-␦ and ␣-⑀ (or ␣-␥) subunits of the receptor. Full activation of the nAChR 1 requires simultaneous binding of two agonist molecules, but antagonists block activation by occupying only one of the two sites.Snakes of the Elapidae and Hydrophidae families are notorious for producing toxins that target nicotinic receptors (7). These small proteins of 57-80 amino acids are commonly called "3-fingered" snake toxins for their characteristic three loop topology, with each of the three fingers extending from a core "knuckle" region consisting of four conserved disulfide bonds. Three-fingered toxins such as ␣-bungarotoxin have been used to probe the nAChR for over 30 years (8). On the other hand, the Viperidae family of snakes does not make 3-fingered toxins and were generally believed not...

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Determination of three-dimensional solution structure of waglerin I, a toxin from Trimeresurus wagleri, using 2D-NMR and molecular dynamics simulation

Cited by 10 publications

References 22 publications

Azemiopsin from Azemiops feae Viper Venom, a Novel Polypeptide Ligand of Nicotinic Acetylcholine Receptor

Azemiopsin from Azemiops feae Viper Venom, a Novel Polypeptide Ligand of Nicotinic Acetylcholine Receptor

End-Plate Acetylcholine Receptor: Structure, Mechanism, Pharmacology, and Disease

Identification of Residues at the α and ε Subunit Interfaces Mediating Species Selectivity of Waglerin-1 for Nicotinic Acetylcholine Receptors

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