Pentameric ligand-gated ion channels: insights from computation

Salari, Reza; Murlidaran, Sruthi; Brannigan, Grace

doi:10.1080/08927022.2014.896462

Cited by 13 publications

(6 citation statements)

References 92 publications

(140 reference statements)

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“…Similar questions apply to ion channels with carboxylate functional groups in their permeation pathways, such as pentameric ligand-gated ion channels and channelrhodopsins. 50,51 Together with prior works, 2,21,52–57 studies like the ones presented here may help resolve those questions for ion transport channels in future work.…”

Section: Discussionmentioning

confidence: 68%

Carboxylate binding prefers two cations to one

Stevens

Rempe

2022

Phys. Chem. Chem. Phys.

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Section: Discussionmentioning

confidence: 68%

Carboxylate binding prefers two cations to one

Stevens

Rempe

2022

Phys. Chem. Chem. Phys.

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“…MD models the physical movements of the system as a function of time by solving Newton’s equations of motion, whereas MC generates an ensemble of configurations according to the corresponding Boltzmann distribution. Such simulations allow one to further characterize the conformational rearrangements occurring upon ligand binding and their connection with ion conduction [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. In combination with enhanced sampling methods and/or free energy calculations, MD can also provide an estimate of the ligand affinity (e.g., binding energy differences between the two forms of the photoswitch or between two photoswitchable ligands), as well as molecular insights into the energetic determinants of binding (e.g., to identify the most suitable position for introducing a reactive Cys for PTL covalent attachment).…”

Section: Computational Modelingmentioning

confidence: 99%

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Nin‐Hill

Mueller

Molteni

et al. 2021

IJMS

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The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach.

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“…Additional candidate binding sites have been observed in more remote members of the pLGIC family that belong to evolutionary distant organisms and share in part low sequence identity. Their 3D architecture reveals that the overall structural features are conserved from bacteria to complex eukaryotes ( Supplementary Figure S1 ) ( Salari et al, 2014 ). Moreover, cholesterol and derivatives thereof have been identified in a number of structures ( Laverty et al, 2017 ; Walsh et al, 2018 ; Zhao et al, 2021 ; Zhu and Gouaux, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

Koniuszewski

Vogel

Bampali

et al. 2022

Front. Mol. Biosci.

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Background: Human pentameric ligand-gated ion channels (pLGICs) comprise nicotinic acetylcholine receptors (nAChRs), 5-hydroxytryptamine type 3 receptors (5-HT3Rs), zinc-activated channels (ZAC), γ-aminobutyric acid type A receptors (GABAARs) and glycine receptors (GlyRs). They are recognized therapeutic targets of some of the most prescribed drugs like general anesthetics, anxiolytics, smoking cessation aids, antiemetics and many more. Currently, approximately 100 experimental structures of pLGICs with ligands bound exist in the protein data bank (PDB). These atomic-level 3D structures enable the generation of a comprehensive binding site inventory for the superfamily and the in silico prediction of binding site properties.Methods: A panel of high throughput in silico methods including pharmacophore screening, conformation analysis and descriptor calculation was applied to a selection of allosteric binding sites for which in vitro screens are lacking. Variant abundance near binding site forming regions and computational docking complement the approach.Results: The structural data reflects known and novel binding sites, some of which may be unique to individual receptors, while others are broadly conserved. The membrane spanning domain, comprising four highly conserved segments, contains ligand interaction sites for which in vitro assays suitable for high throughput screenings are critically lacking. This is also the case for structurally more variable novel sites in the extracellular domain. Our computational results suggest that the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) can utilize multiple pockets which are likely to exist on most superfamily members.Conclusion: With this study, we explore the potential for polypharmacology among pLGICs. Our data suggest that ligands can display two forms of promiscuity to an extent greater than what has been realized: 1) Ligands can interact with homologous sites in many members of the superfamily, which bears toxicological relevance. 2) Multiple pockets in distinct localizations of individual receptor subtypes share common ligands, which counteracts efforts to develop selective agents. Moreover, conformational states need to be considered for in silico drug screening, as certain binding sites display considerable flexibility. In total, this work contributes to a better understanding of polypharmacology across pLGICs and provides a basis for improved structure guided in silico drug development and drug derisking.

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Pentameric ligand-gated ion channels: insights from computation

Cited by 13 publications

References 92 publications

Carboxylate binding prefers two cations to one

Carboxylate binding prefers two cations to one

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

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