Membrane-mediated interaction of non-conventional snake three-finger toxins with nicotinic acetylcholine receptors

Шенкарев, Захар О.; Chesnokov, Yuri M; Zaigraev, Maxim M; Chugunov, Anton O.; Kulbatskii, Dmitrii S.; Kocharovskaya, Milita V.; Paramonov, Alexander S.; Bychkov, Maxim L.; Shulepko, Mikhail A.; Nolde, Dmitry E.; Kamyshinsky, Roman A.; Yablokov, E. O.; Ivanov, A. S.; Kirpichnikov, Mikhaǐl P.; Lyukmanova, Ekaterina N.

doi:10.1038/s42003-022-04308-6

Cited by 11 publications

(4 citation statements)

References 71 publications

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“…The 'Head' region of TFPs also has a disordered structure (Figure 3c) and can be considered an auxiliary binding site regulating TFP's interaction with other supplementary partners necessary for the function of the 'main' receptor. These supplementary partners can be either the cell membrane surrounding the nicotinic acetylcholine receptor [53,54] or other receptors, for example, receptor-tyrosine kinases in the case of nicotinic acetylcholine receptors and the human SLURP-1 protein in cancer cells [51]. Here, on the example of mambalgin-2, we revealed an additional 'application' of the 'head' region of TFPs: the regulation of the interaction selectivity between various types of acid-sensing channels.…”

Section: Discussionmentioning

confidence: 83%

Molecular Basis for Mambalgin-2 Interaction with Heterotrimeric α-ENaC/ASIC1a/γ-ENaC Channels in Cancer Cells

Lyukmanova,

Zaigraev,

Kulbatskii

et al. 2023

Toxins

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Cancer progression is characterized by microenvironmental acidification. Tumor cells adapt to low environmental pH by activating acid-sensing trimeric ion channels of the DEG/ENaC family. The α-ENaC/ASIC1a/γ-ENaC heterotrimeric channel is a tumor-specific acid-sensing channel, and its targeting can be considered a new strategy for cancer therapy. Mambalgin-2 from the Dendroaspis polylepis venom inhibits the α-ENaC/ASIC1a/γ-ENaC heterotrimer more effectively than the homotrimeric ASIC1a channel, initially proposed as the target of mambalgin-2. Although the molecular basis of such mambalgin selectivity remained unclear. Here, we built the models of the complexes of mambalgin-2 with the α-ENaC/ASIC1a/γ-ENaC and ASIC1a channels, performed MD and predicted the difference in the binding modes. The importance of the ‘head’ loop region of mambalgin-2 for the interaction with the hetero-, but not with the homotrimeric channel was confirmed by site-directed mutagenesis and electrophysiology. A new mode of allosteric regulation of the ENaC channels by linking the thumb domain of the ASIC1a subunit with the palm domain of the γ-ENaC subunit was proposed. The data obtained provide new insights into the regulation of various types of acid-sensing ion channels and the development of new strategies for cancer treatment.

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Section: Discussionmentioning

confidence: 83%

Molecular Basis for Mambalgin-2 Interaction with Heterotrimeric α-ENaC/ASIC1a/γ-ENaC Channels in Cancer Cells

Lyukmanova,

Zaigraev,

Kulbatskii

et al. 2023

Toxins

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“…The data available to date indicate that the WTX central loop II (Fig. 1) makes the greatest contribution to the interaction with nAChR [ 7 , 8 ]. This loop interacts with the acetylcholine-binding pocket of nAChR, whereas loop I presumably interacts with the membrane surrounding the receptor [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…1) makes the greatest contribution to the interaction with nAChR [ 7 , 8 ]. This loop interacts with the acetylcholine-binding pocket of nAChR, whereas loop I presumably interacts with the membrane surrounding the receptor [ 8 ]. An important role of loop II in the interaction with nAChR was previously shown for snake α-neurotoxins [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Synthetic Peptide Fragments of the Wtx Toxin Reduce Blood Pressure in Rats under General Anesthesia

Severyukhina,

Ismailova,

Shaykhutdinova

et al. 2023

Dokl Biochem Biophys

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Previously, it was shown that the non-conventional toxin WTX from the venom of the cobra Naja kaouthia, when administered intravenously, caused a decrease in blood pressure (BP) and an increase in heart rate (HR) in rats [13]. To identify the site of the toxin molecule responsible for these effects, we studied the influence of synthetic peptide fragments of the WTX on BP and HR in normotensive male Sprague–Dawley rats under general anesthesia induced by Telazol and Xylazine. It was found that peptides corresponding to the WTX central polypeptide loop, stabilized by a disulfide bond, at intravenous injection at concentrations from 0.1 to 1.0 mg/mL caused a dose-dependent decrease in BP, with the HR increasing only in the first 5–10 min after administration. Thus, WTX fragments corresponding to the central polypeptide loop reproduce the decrease in blood pressure caused by the toxin.

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“…One such toxin, namely WTX (weak toxin), from Naja kaouthia snake venom, was shown to inhibit both muscle-type and α7 nAChRs at micromolar concentrations [ 10 ] and because of its low toxicity, may be considered for possible medical applications. Recent cryo-electron microscopy determination of the WTX structure in complex with the extracellular domain of the α7 nAChR [ 11 ] may open the way for the design of medically useful variants.…”

Section: Snake α-Neurotoxins and Ly6/upar Proteins As Research Tools ...mentioning

confidence: 99%

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

Shelukhina

Siniavin

Kasheverov

et al. 2023

IJMS

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Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, affecting the production of cytokines. The analgesic properties of α7 nAChR-selective compounds are mostly based on the activation of the cholinergic anti-inflammatory pathway. The molecular mechanism of neuropathic pain relief mediated by the inhibition of α9-containing nAChRs is not fully understood yet, but the role of immune factors in this process is becoming evident. To obtain appropriate drugs, a search of selective agonists, antagonists and modulators of α7- and α9-containing nAChRs is underway. The naturally occurring three-finger snake α-neurotoxins and mammalian Ly6/uPAR proteins, as well as neurotoxic peptides α-conotoxins, are not only sophisticated tools in research on nAChRs but are also considered as potential medicines. In particular, the inhibition of the α9-containing nAChRs by α-conotoxins may be a pathway to alleviate neuropathic pain. nAChRs are involved in the inflammation processes during AIDS and other viral infections; thus they can also be means used in drug design. In this review, we discuss the role of α7- and α9-containing nAChRs in the immune processes and in pain.

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Membrane-mediated interaction of non-conventional snake three-finger toxins with nicotinic acetylcholine receptors

Cited by 11 publications

References 71 publications

Molecular Basis for Mambalgin-2 Interaction with Heterotrimeric α-ENaC/ASIC1a/γ-ENaC Channels in Cancer Cells

Molecular Basis for Mambalgin-2 Interaction with Heterotrimeric α-ENaC/ASIC1a/γ-ENaC Channels in Cancer Cells

Synthetic Peptide Fragments of the Wtx Toxin Reduce Blood Pressure in Rats under General Anesthesia

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

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