Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor

Gharpure, Anant; Teng, Jian; Zhuang, Yinghong; Noviello, Colleen; Walsh, Richard M.; Cabuco, Rico; Howard, Rebecca J.; Zaveri, Nurulain T.; Lindahl, Erik; Hibbs, Ryan

doi:10.1016/j.neuron.2019.07.030

Cited by 158 publications

(162 citation statements)

References 98 publications

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“…Further rearrangement to the open state contracts both the β1-β2/M2 and F/M2-M3 clefts (Fig 5C, Appendix Fig S5A). The same pattern is evident in agonist-bound versus apo structures of ELIC, GluCl, glycine and nicotinic receptors (Appendix Fig S5B-E) [49]–[54], and in open/desensitized versus inhibitor-bound structures of DeCLIC and GABA A receptors (Appendix Fig S5F-G) [55], [56]. A noted exception is the 5-HT 3A receptor, in which loop F instead translocates outward and the M2-M3 loop inward (Appendix Fig S5H), suggesting that apparent open states reported for 5-HT 3A may sample a divergent mechanism of gating [57]–[59].…”

Section: Discussionmentioning

confidence: 60%

Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations

Rovšnik

Zhuang

Forsberg

et al. 2021

Preprint

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Ligand-gated ion channels are critical mediators of electrochemical signal transduction across evolution. Biophysical and pharmacological characterization of these receptor proteins relies on high-quality structures in multiple, subtly distinct functional states. However, structural data in this family remain limited, particularly for resting and intermediate states on the activation pathway. Here we report cryo-electron microscopy (cryo-EM) structures of the proton-activated Gloeobacter violaceus ligand-gated ion channel (GLIC) under three pH conditions. Decreased pH was associated with improved resolution and sidechain rearrangements at the subunit/domain interface, particularly involving functionally important residues in the β1-β2 and M2-M3 loops. Molecular dynamics simulations substantiated flexibility in the closed-channel extracellular domains relative to the transmembrane ones, and supported electrostatic remodeling around E35 and E243 in proton-induced gating. Exploration of secondary cryo-EM classes further indicated a low-pH population with an expanded pore. These results support a dissection of protonation and activation steps in pH-stimulated conformational cycling in GLIC, including interfacial rearrangements largely conserved in the pentameric channel family.

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Section: Discussionmentioning

confidence: 60%

Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations

Rovšnik

Zhuang

Forsberg

et al. 2021

Preprint

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“…Three enzymes were selected for the construction of homology models: AChE, ACh, and Cht. The template enzymes were: AChE from Anopheles gambiae (PDB ID: 5YDH) [ 116 ], ACh from Homo sapiens (PDB ID: 6PV7) [ 117 ], and ChtII from Ostrinia furnicalis (PDB ID: 6JAV) [ 107 ]. The enzyme models were built using the molecular homology modeling method in the MODELLER 9.20 software [ 118 ].…”

Section: Methodsmentioning

confidence: 99%

In Silico Studies of Lamiaceae Diterpenes with Bioinsecticide Potential against Aphis gossypii and Drosophila melanogaster

et al. 2021

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Background: The growing demand for agricultural products has led to the misuse/overuse of insecticides; resulting in the use of higher concentrations and the need for ever more toxic products. Ecologically, bioinsecticides are considered better and safer than synthetic insecticides; they must be toxic to the target organism, yet with low or no toxicity to non-target organisms. Many plant extracts have seen their high insecticide potential confirmed under laboratory conditions, and in the search for plant compounds with bioinsecticidal activity, the Lamiaceae family has yielded satisfactory results. Objective: The aim of our study was to develop computer-assisted predictions for compounds with known insecticidal activity against Aphis gossypii and Drosophila melanogaster. Results and conclusion: Structure analysis revealed ent-kaurane, kaurene, and clerodane diterpenes as the most active, showing excellent results. We also found that the interactions formed by these compounds were more stable, or presented similar stability to the commercialized insecticides tested. Overall, we concluded that the compounds bistenuifolin L (1836) and bistenuifolin K (1931), were potentially active against A. gossypii enzymes; and salvisplendin C (1086) and salvixalapadiene (1195), are potentially active against D. melanogaster. We observed and highlight that the diterpenes bistenuifolin L (1836), bistenuifolin K (1931), salvisplendin C (1086), and salvixalapadiene (1195), present a high probability of activity and low toxicity against the species studied.

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“…To determine the effects of inter-subunit contacts between residues on the binding interfaces, we employed a network interaction analysis implemented in the software Cytoscape [57]. Differences in inter-subunit contacts help reveal changes in the relative orientations of the subunits at toxin-bound interfaces, which may be related to the capacity of the toxins to inhibit nAChR function [36,[58][59][60].…”

Section: Inter-subunit Contacts At the α3(+)β2(−) And β2(+)α3(−) Intementioning

confidence: 99%

Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations

2020

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Notably, α-conotoxins with carboxy-terminal (C-terminal) amidation are inhibitors of the pentameric nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets for neurological diseases and disorders. The (α3)2(β2)3 nAChR subunit arrangement comprises a pair of α3(+)β2(−) and β2(+)α3(−) interfaces, and a β2(+)β2(−) interface. The β2(+)β2(−) interface has been suggested to have higher agonist affinity relative to the α3(+)β2(−) and β2(+)α3(−) interfaces. Nevertheless, the interactions formed by these subunit interfaces with α-conotoxins are not well understood. Therefore, in order to address this, we modelled the interactions between α-conotoxin LsIA and the α3β2 subtype. The results suggest that the C-terminal carboxylation of LsIA predominantly influenced the enhanced contacts of the conotoxin via residues P7, P14 and C17 on LsIA at the α3(+)β2(−) and β2(+)α3(−) interfaces. However, this enhancement is subtle at the β2(+)β2(−) site, which can compensate the augmented interactions by LsIA at α3(+)β2(−) and β2(+)α3(−) binding sites. Therefore, the divergent interactions at the individual binding interface may account for the minor changes in binding affinity to α3β2 subtype by C-terminal carboxylation of LsIA versus its wild type, as shown in previous experimental results. Overall, these findings may facilitate the development of new drug leads or subtype-selective probes.

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Agonist Selectivity and Ion Permeation in the α3β4 Ganglionic Nicotinic Receptor

Cited by 158 publications

References 98 publications

Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations

Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations

In Silico Studies of Lamiaceae Diterpenes with Bioinsecticide Potential against Aphis gossypii and Drosophila melanogaster

Interactions of the α3β2 Nicotinic Acetylcholine Receptor Interfaces with α-Conotoxin LsIA and its Carboxylated C-terminus Analogue: Molecular Dynamics Simulations

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