Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure–activity relationships studies

Peng, Wei; Ding, Fei

doi:10.1016/j.ejps.2015.05.005

Cited by 5 publications

(6 citation statements)

References 81 publications

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“…Another region that exhibits marginally higher RMSF for amidated LsIA-bound α7 is the loop C region, which forms part of the canonical agonist binding site and, in the α-subunits of nAChRs, is composed of a β hairpin with a twin Cys motif at the edge of the loop. This enhanced fluctuation is in accordance with previous studies on nAChRs, including those for apo α7 and α7-antagonist-bound complexes [53]. Nonetheless, the higher RMSF of both loop C and the juxtamembrane Cys-loop region, for amidated LsIA, is consistent with the present notion that movements in these two areas are strongly coupled, and is required for transmission of structural effects due to agonist (or antagonist) binding from the ECD to the transmembrane pore.…”

Section: Resultssupporting

confidence: 93%

“…These plots demonstrate the greatest flexibility in the Cys-loop, and are similar to the RMSF results of several previous studies, such as that of α-ImI bound form, by Yu et al via computational simulations [18], who found that the Cys-loop RMSF increased compared with apo human α7 nAChR. There is also relatively high flexibility of β1/β2 loop and β10 strand, similar to previous studies [53].…”

Section: Resultssupporting

confidence: 88%

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Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies

Wen¹,

Hung²

2019

Marine Drugs

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α-Conotoxins selectively bind to nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets due to their important role in signaling transmission in excitable cells. A previous experimental study has demonstrated that carboxylation of the C-terminal of α-conotoxin LsIA reduces its potency to inhibit human α7 nAChR relative to naturally amidated LsIA. However, little is known about the contribution of conformational changes in the receptor and interactions, induced by C-terminal amidation/carboxylation of conotoxins, to selective binding to nAChRs, since most conotoxins and some disulfide-rich peptides from other conotoxin subfamilies possess a naturally amidated C-terminal. In this study, we employ homology modeling and molecular dynamics (MD) simulations to propose the determinants for differential interactions between amidated and carboxylated LsIAs with α7 nAChR. Our findings indicate an overall increased number of contacts favored by binding of amidated LsIA versus its carboxylated counterpart. Toxin-receptor pairwise interactions, which may play a role in enhancing the potency of the former, include ARG10-TRP77, LEU141 and CYS17-GLN79 via persistent hydrogen bonds and cation-π interactions, which are weakened in the carboxylated form due to a strong intramolecular salt-bridge formed by ARG10 and carboxylated C-terminus. The binding of amidated LsIA also induces enhanced movements in loop C and the juxtamembrane Cys-loop that are closely associated with receptor function. Additionally, the impacts of binding of LsIA on the overall structure and inter-subunit contacts were examined using inter-residue network analysis, suggesting a clockwise tilting of the α7 C and F loops upon binding to carboxylated LsIA, which is absent for amidated LsIA binding. The predicted molecular mechanism of LsIA binding to the α7 receptor may provide new insights into the important role of the C-terminal in the binding potency of conotoxins at neuronal nAChRs for pharmacological purposes.

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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 88%

Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies

Wen¹,

Hung²

2019

Marine Drugs

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“…Neuronal nAChRs also are expressed in numerous other cell types and tissues, including endothelial cells, gastrointestinal tissues, glia, immune cells, keratinocytes, urinary bladder tissues, reproductive organs, and respiratory tissues [ 85 - 96 ]. In addition to the acetylcholine binding sites [ 20 , 40 ] other binding sites on nAChRs, such as the cholesterol-binding sites in M1–M4 segments [ 74 , 97 ] the α-neurotoxin-binding sites in the central loop C of the α subunit, [ 98 ] and binding sites for methyllycaconitine and synthetic antagonists [ 99 ] have been identified. As a result of their roles in the propagation of action potentials, cognitive function, and diverse central nervous system pathologies, they are hypothetical targets for many drugs and toxins [ 84 , 100 ].…”

Section: The Structure and Diversity Of Nachrsmentioning

confidence: 99%

Insights Into Nicotinic Receptor Signaling in Nicotine Addiction: Implications for Prevention and Treatment

Liu

2018

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BackgroundNicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop ligand-gated ion-channel (LGIC) superfamily, which also includes the GABA, glycine, and serotonin receptors. Many nAChR subunits have been identified and shown to be involved in signal transduction on binding to them of either the neurotransmitter acetylcholine or exogenous ligands such as nicotine. The nAChRs are pentameric assemblies of homologous subunits surrounding a central pore that gates cation flux, and they are expressed at neuromuscular junctions throughout the nervous system.Methods and ResultsBecause different nAChR subunits assemble into a variety of pharmacologically distinct receptor subtypes, and different nAChRs are implicated in various physiological functions and pathophysiological conditions, nAChRs represent potential molecular targets for drug addiction and medical therapeutic research. This review intends to provide insights into recent advances in nAChR signaling, considering the subtypes and subunits of nAChRs and their roles in nicotinic cholinergic systems, including structure, diversity, functional allosteric modulation, targeted knockout mutations, and rare variations of specific subunits, and the potency and functional effects of mutations by focusing on their effects on nicotine addiction (NA) and smoking cessation (SC). Furthermore, we review the possible mechanisms of action of nAChRs in NA and SC based on our current knowledge.ConclusionUnderstanding these cellular and molecular mechanisms will lead to better translational and therapeutic operations and outcomes for the prevention and treatment of NA and other drug addictions, as well as chronic diseases, such as Alzheimer’s and Parkinson’s. Finally, we put forward some suggestions and recommendations for therapy and treatment of NA and other chronic diseases.

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“…This pharmacophore includes a basic amine protonated at physiological pH for cation−π interaction, a hydrophobic aromatic part for π–π interaction, and a linker that acts as a hydrogen bond acceptor (Figure ). Peng et al reported that hydrogen bonds, π–π interactions, and hydrophobic interactions are important binding interactions for α7 nAChR antagonists . Further, they identified specific amino acid residues involved in the interaction with the antagonist from in silico systems, such as Tyr93, Lys143, Trp147, Tyr188, and Tyr195 in the principal subunit as well as Trp55 and Leu118 in the complementary subunit.…”

Section: The Development Of α7 Nicotinic Acetylcholine Receptor Antag...mentioning

confidence: 99%

“…64 Peng et al reported that hydrogen bonds, π−π interactions, and hydrophobic interactions are important binding interactions for α7 nAChR antagonists. 65 Further, they identified specific amino acid residues involved in the interaction with the antagonist from in silico systems, such as Tyr93, Lys143, Trp147, Tyr188, and Tyr195 in the principal subunit as well as Trp55 and Leu118 in the complementary subunit. The most crucial residues for antagonist recognition were Ty93, Trp147, and Tyr188 in the principal subunit, as determined by site-directed α7 nAChR mutagenesis.…”

Section: ■ the Development Of α7 Nicotinic Acetylcholine Receptor Ant...mentioning

confidence: 99%

Targeting Alpha7 Nicotinic Acetylcholine Receptors in Lung Cancer: Insights, Challenges, and Therapeutic Strategies

Arunrungvichian,

Vajragupta,

Hayakawa

et al. 2023

ACS Pharmacol. Transl. Sci.

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Alpha7 nicotinic acetylcholine receptor (α7 nAChR) is an ion-gated calcium channel that plays a significant role in various aspects of cancer pathogenesis, particularly in lung cancer. Preclinical studies have elucidated the molecular mechanism underlying α7 nAChR-associated lung cancer proliferation, chemotherapy resistance, and metastasis. Understanding and targeting this mechanism are crucial for developing therapeutic interventions aimed at disrupting α7 nAChR-mediated cancer progression and improving treatment outcomes. Drug research and discovery have determined natural compounds and synthesized chemical antagonists that specifically target α7 nAChR. However, approved α7 nAChR antagonists for clinical use are lacking, primarily due to challenges related to achieving the desired selectivity, efficacy, and safety profiles required for effective therapeutic intervention. This comprehensive review provided insights into the molecular mechanisms associated with α7 nAChR and its role in cancer progression, particularly in lung cancer. Furthermore, it presents an update on recent evidence about α7 nAChR antagonists and addresses the challenges encountered in drug research and discovery in this field.

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Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure–activity relationships studies

Cited by 5 publications

References 81 publications

Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies

Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies

Insights Into Nicotinic Receptor Signaling in Nicotine Addiction: Implications for Prevention and Treatment

Targeting Alpha7 Nicotinic Acetylcholine Receptors in Lung Cancer: Insights, Challenges, and Therapeutic Strategies

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