Histidine 186 of the nicotinic acetylcholine receptor α subunit requires the presence of the 192–193 disulfide bridge to interact with α-bungarotoxin

Testai, Fernando D.; Venera, Graciela Delia; Peña, Clara; Bonino, M.J. Biscoglio De Jimenez

doi:10.1016/s0197-0186(99)00099-6

Cited by 12 publications

(8 citation statements)

References 21 publications

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“…The C-C bond in the nAChR binding region does not participate directly in analyte-ligand binding [12,36,37], thus replacement to S-S is not expected to have any effect on the analyte-ligand complex formation. However, the presence of the C-C bridge is key in the conformation of the interaction site of whole receptors [38]. As such, we suggest direct comparisons of kinetics data, such as Ka or KD, between nAChR mimotopes and whole receptor testing should be avoided, or at least approached with caution.…”

Section: (B) Mimotope Production and Preparationmentioning

confidence: 99%

Electrostatic resistance to alpha-neurotoxins conferred by charge reversal mutations in nicotinic acetylcholine receptors

Harris

Fry

2021

Proc. R. Soc. B.

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The evolution of venom resistance through coevolutionary chemical arms races has arisen multiple times throughout animalia. Prior documentation of resistance to snake venom α-neurotoxins consists of the N-glycosylation motif or the hypothesized introduction of arginine at positions 187 at the α-1 nicotinic acetylcholine receptor orthosteric site. However, no further studies have investigated the possibility of other potential forms of resistance. Using a biolayer interferometry assay, we first confirm that the previously hypothesized resistance conferred by arginine at position 187 in the honey badger does reduce binding to α-neurotoxins, which has never been functionally tested. We further discovered a novel form of α-neurotoxin resistance conferred by charge reversal mutations, whereby a negatively charged amino acid is replaced by the positively charged amino acid lysine. As venom α-neurotoxins have evolved strong positive charges on their surface to facilitate binding to the negatively charged α-1 orthosteric site, these mutations result in a positive charge/positive charge interaction electrostatically repelling the α-neurotoxins. Such a novel mechanism for resistance has gone completely undiscovered, yet this form of resistance has convergently evolved at least 10 times within snakes. These coevolutionary innovations seem to have arisen through convergent phenotypes to ultimately evolve a similar biophysical mechanism of resistance across snakes.

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Section: (B) Mimotope Production and Preparationmentioning

confidence: 99%

Electrostatic resistance to alpha-neurotoxins conferred by charge reversal mutations in nicotinic acetylcholine receptors

Harris

Fry

2021

Proc. R. Soc. B.

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“…The Cys-Cys bond in the nAChR binding region does not participate directly in analyte-ligand binding [57][58][59], thus replacement to Ser-Ser is not expected to have any effect on the analyte-ligand complex formation. However, the presence of the Cys-Cys bridge is key in the conformation of the interaction site of whole receptors [60]. Therefore, we suggest direct comparisons of kinetics data, such as K a or KD, between nAChR mimotopes and whole-receptor testing should be avoided or at least approached with caution.…”

Section: Mimotope Production and Preparationmentioning

confidence: 99%

An Appetite for Destruction: Detecting Prey-Selective Binding of α-Neurotoxins in the Venom of Afro-Asian Elapids

Harris

Zdenek

Harrich

et al. 2020

Toxins

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Prey-selective venoms and toxins have been documented across only a few species of snakes. The lack of research in this area has been due to the absence of suitably flexible testing platforms. In order to test more species for prey specificity of their venom, we used an innovative taxonomically flexible, high-throughput biolayer interferometry approach to ascertain the relative binding of 29 α-neurotoxic venoms from African and Asian elapid representatives (26 Naja spp., Aspidelaps scutatus, Elapsoidea boulengeri, and four locales of Ophiophagus hannah) to the alpha-1 nicotinic acetylcholine receptor orthosteric (active) site for amphibian, lizard, snake, bird, and rodent targets. Our results detected prey-selective, intraspecific, and geographical differences of α-neurotoxic binding. The results also suggest that crude venom that shows prey selectivity is likely driven by the proportions of prey-specific α-neurotoxins with differential selectivity within the crude venom. Our results also suggest that since the α-neurotoxic prey targeting does not always account for the full dietary breadth of a species, other toxin classes with a different pathophysiological function likely play an equally important role in prey immobilisation of the crude venom depending on the prey type envenomated. The use of this innovative and taxonomically flexible diverse assay in functional venom testing can be key in attempting to understanding the evolution and ecology of α-neurotoxic snake venoms, as well as opening up biochemical and pharmacological avenues to explore other venom effects.

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“…The C–C bond in the nAChR binding region does not participate directly in analyte-ligand binding [ 51 , 71 , 72 ], thus replacement to S–S is not expected to have any effect on the analyte-ligand complex formation. However, the presence of the C–C bridge is key in the conformation of the interaction site of whole receptors [ 73 ]. As such, we suggest direct comparisons of kinetics data, such as Ka or KD, between nAChR mimotopes and whole receptor testing should be avoided, or at least approached with caution.…”

Section: Methodsmentioning

confidence: 99%

Monkeying around with venom: an increased resistance to α-neurotoxins supports an evolutionary arms race between Afro-Asian primates and sympatric cobras

2021

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Background Snakes and primates have a multi-layered coevolutionary history as predators, prey, and competitors with each other. Previous work has explored the Snake Detection Theory (SDT), which focuses on the role of snakes as predators of primates and argues that snakes have exerted a selection pressure for the origin of primates’ visual systems, a trait that sets primates apart from other mammals. However, primates also attack and kill snakes and so snakes must simultaneously avoid primates. This factor has been recently highlighted in regard to the movement of hominins into new geographic ranges potentially exerting a selection pressure leading to the evolution of spitting in cobras on three independent occasions. Results Here, we provide further evidence of coevolution between primates and snakes, whereby through frequent encounters and reciprocal antagonism with large, diurnally active neurotoxic elapid snakes, Afro-Asian primates have evolved an increased resistance to α-neurotoxins, which are toxins that target the nicotinic acetylcholine receptors. In contrast, such resistance is not found in Lemuriformes in Madagascar, where venomous snakes are absent, or in Platyrrhini in the Americas, where encounters with neurotoxic elapids are unlikely since they are relatively small, fossorial, and nocturnal. Within the Afro-Asian primates, the increased resistance toward the neurotoxins was significantly amplified in the last common ancestor of chimpanzees, gorillas, and humans (clade Homininae). Comparative testing of venoms from Afro-Asian and American elapid snakes revealed an increase in α-neurotoxin resistance across Afro-Asian primates, which was likely selected against cobra venoms. Through structure-activity studies using native and mutant mimotopes of the α-1 nAChR receptor orthosteric site (loop C), we identified the specific amino acids responsible for conferring this increased level of resistance in hominine primates to the α-neurotoxins in cobra venom. Conclusion We have discovered a pattern of primate susceptibility toward α-neurotoxins that supports the theory of a reciprocal coevolutionary arms-race between venomous snakes and primates.

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Histidine 186 of the nicotinic acetylcholine receptor α subunit requires the presence of the 192–193 disulfide bridge to interact with α-bungarotoxin

Cited by 12 publications

References 21 publications

Electrostatic resistance to alpha-neurotoxins conferred by charge reversal mutations in nicotinic acetylcholine receptors

Electrostatic resistance to alpha-neurotoxins conferred by charge reversal mutations in nicotinic acetylcholine receptors

An Appetite for Destruction: Detecting Prey-Selective Binding of α-Neurotoxins in the Venom of Afro-Asian Elapids

Monkeying around with venom: an increased resistance to α-neurotoxins supports an evolutionary arms race between Afro-Asian primates and sympatric cobras

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