Polypharmacology profiles and phylogenetic analysis of three-finger toxins from mamba venom: Case of aminergic toxins

Blanchet, Guillaume; Collet, Guillaume; Mourier, Gilles; Gilles, Nicolas; Fruchart-Gaillard, Carole; Marcon, Elodie; Servent, Denis

doi:10.1016/j.biochi.2014.04.009

Cited by 27 publications

(39 citation statements)

References 61 publications

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“…Previously published phylogenetic analysis showed that the aminergic toxins are a functional family specifically developed in the mamba venoms and that a high sequence identity is shared among them (at least 70%, Fig. 1A) 19 . Based on these results, the maximum likelihood (ML) tree of the mamba aminergic toxins was reconstructed (Fig.…”

Section: Resultsmentioning

confidence: 88%

“…1B). The two MTLP 1 and 2 from Naja kaouthia were considered as an out group 19 . The ML methodology allows also the reconstruction of the sequences at each nodes of the tree, also called ancestral (B) Maximum likelihood tree and associated function of the aminergic toxins.…”

Section: Resultsmentioning

confidence: 99%

“…Affinity constant (pKi ± SEM) of MT3, ρ-Da1b and AncTx5 toxins for muscarinic (M1, M4), adrenergic (α 1A , α 1B , α 1D , α 2A , α 2CB , α 2C ) and dopaminergic (D3) receptors. a: [19].…”

Section: Discussionmentioning

confidence: 99%

“…The six AncTxs were first screened on the 12 previously identified aminergic receptor targets reported for the aminergic toxins (namely M 1 to M 5 muscarinic receptor subtypes, all three α1 and α2 adrenoceptor subtypes and the dopamine D 3 subtype) by heterologous inhibition experiment as described in Blanchet et al 19 . In short, 5 µM of each AncTxs were incubated (in duplicate) with a fixed amount of membrane preparation and a fixed concentration of a specific radioligand in 96-wells plate with 100 µl as final volume for 20h at RT.…”

Section: Methodsmentioning

confidence: 99%

“…The black widow spider and the gila monster provide further examples of GPCRs interacting toxins, namely, α-latrotoxin interacting with the latrophilin receptor 11 and exenatide, exploited as an anti-diabetic drug 12 , that targets the GLP-1 receptor, respectively. In addition, mamba venoms contain aminergic toxins that recognize various bioaminergic receptors [13][14][15][16][17][18][19] . Aminergic toxins belong to the three-finger fold toxin (3FT) superfamily, a structural fold known to support a large diversity of biological functions 20 .…”

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confidence: 99%

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Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins

Blanchet

Stura

Mourier

et al. 2018

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Mamba venoms contain a multiplicity of three-finger fold aminergic toxins known to interact with various α-adrenergic, muscarinic and dopaminergic receptors with different pharmacological profiles. In order to generate novel functions on this structural scaffold and to avoid the daunting task of producing and screening an overwhelming number of variants generated by a classical protein engineering strategy, we accepted the challenge of resurrecting ancestral proteins, likely to have possessed functional properties. This innovative approach that exploits molecular evolution models to efficiently guide protein engineering, has allowed us to generate a small library of six ancestral toxin (AncTx) variants and associate their pharmacological profiles to key functional substitutions. Among these variants, we identified AncTx1 as the most α 1A -adrenoceptor selective peptide known to date and AncTx5 as the most potent inhibitor of the three α2 adrenoceptor subtypes. Three positions in the ρ-Da1a evolutionary pathway, positions 28, 38 and 43 have been identified as key modulators of the affinities for the α 1 and α 2C adrenoceptor subtypes. Here, we present a first attempt at rational engineering of the aminergic toxins, revealing an epistasis phenomenon.Evolutionary processes of venomous animals have selected enzymes and disulfide-rich peptides in their venoms to improve their ability to subdue their prey and defend against predators. These compounds act predominantly on few, well characterized and physiologically-relevant molecular targets of the envenomed animals 1 . Recruited by convergent evolution, toxins impact mainly the haemostatic, nervous and cardiovascular systems 2 . Some toxins present in venoms, in spite of their debilitating effects, have become live-saving drugs [3][4][5] . To exert their biological activities, toxins interact mainly with ion channels, coagulation factors, nicotinic receptors, cell membrane or enzymes but only rarely with the most important class of physiological targets, i.e, the G protein-coupled receptors (GPCRs) 6 . Compared to numerous toxins that act on voltage-gated or ligand-gated ion channels, only a few toxins that interact with GPCRs have been identified. These toxins have been isolated mainly from cone snails venoms such as conopressin interacting with vasopressin receptor 7 , contulakin-G which binds to neurotensin receptor 8 , ρ-conotoxin TIA specific of the α 1A -adrenoceptor 9 and the τ-conotoxin CnVA that interacts with the somatostatin sst3 receptor 10 . The black widow spider and the gila monster provide further examples of GPCRs interacting toxins, namely, α-latrotoxin interacting with the latrophilin receptor 11 and exenatide, exploited as an anti-diabetic drug 12 , that targets the GLP-1 receptor, respectively. In addition, mamba venoms contain aminergic toxins that recognize various bioaminergic receptors [13][14][15][16][17][18][19] . Aminergic toxins belong to the three-finger fold toxin (3FT) superfamily, a structural fold known to support a large diversity of...

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Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins

Blanchet

Stura

Mourier

et al. 2018

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Purification and Characterization of Nk‐3FTx: A Three Finger Toxin from the Venom of North East Indian Monocled Cobra

Das

Sharma

Das

et al. 2015

J Biochem & Molecular Tox

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Snake venom three finger toxins (3FTxs) are a non-enzymatic family of venom proteins abundantly found in elapids. We have purified a 7579.5 ± 0.591 Da 3FTx named as Nk-3FTx from the venom of Naja kaouthia of North East India origin. The primary structure was determined by a combination of N-terminal sequencing and electrospray ionization liquid chromatography-mass spectrometry/mass spectrometry. Biochemical and biological characterization reveal that it is nontoxic to human cell lines and exhibit mild anticoagulant activity when tested on citrated human plasma. Nk-3FTx was found to affect the compound action potential (CAP) and nerve conduction velocity of isolated toad sciatic nerve. This is the first report of a non-conventional 3FTx from Naja kaouthia venom that reduces CAP for its neurotoxic effect. Further studies can be carried out to understand the mechanism of action and to explore its potential therapeutic application.

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Onchidal and fasciculins

Anadón¹,

Martínez-Larrañaga²,

Valerio³

2020

Handbook of Toxicology of Chemical Warfare Agents

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Polypharmacology profiles and phylogenetic analysis of three-finger toxins from mamba venom: Case of aminergic toxins

Cited by 27 publications

References 61 publications

Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins

Ancestral protein resurrection and engineering opportunities of the mamba aminergic toxins

Purification and Characterization of Nk‐3FTx: A Three Finger Toxin from the Venom of North East Indian Monocled Cobra

Onchidal and fasciculins

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