On the Functional Annotation of Open-Channel Structures in the Glycine Receptor

Cerdan, Adrien H.; Cecchini, Marco

doi:10.1016/j.str.2020.05.003

Cited by 11 publications

(13 citation statements)

References 37 publications

(67 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analysis of the ion transmembrane pore during the last 50 ns by the program HOLE (50) indicates that the pore lumen at the constriction point is 2.67 Å with an SD of 0.32 Å. These results indicate that the MD-relaxed structure of GlyR-1 is physically open to chloride; it is structurally consistent with the open-channel state isolated in our previous analysis (15,16); and it presents a pore lumen in excellent agreement with the experimental predictions based on permeability to polyatomic anions (5). In addition, the large fluctuations sampled by MD at the constriction point (fig.…”

Section: Modeling Of the Active Statesupporting

confidence: 77%

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

et al. 2022

Self Cite

View full text Add to dashboard Cite

Glycine receptors (GlyRs) are ligand-gated ion channels mediating signal transduction at chemical synapses. Since the early patch-clamp electrophysiology studies, the details of the ion permeation mechanism have remained elusive. Here, we combine molecular dynamics simulations of a zebrafish GlyR-α1 model devoid of the intracellular domain with mutagenesis and single-channel electrophysiology of the full-length human GlyR-α1. We show that lateral fenestrations between subunits in the extracellular domain provide the main translocation pathway for chloride ions to enter/exit a central water-filled vestibule at the entrance of the transmembrane channel. In addition, we provide evidence that these fenestrations are at the origin of current rectification in known anomalous mutants and design de novo two inward-rectifying channels by introducing mutations within them. These results demonstrate the central role of lateral fenestrations on synaptic neurotransmission.

show abstract

Section: Modeling Of the Active Statesupporting

confidence: 77%

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…More recently, there has been a discussion of the nature of the open-state structure determined using detergent-solubilized GlyR protein, focusing on whether or not this may represent as a “superopen” state, the relationship of which to the physiological open state in a cell membrane (i.e., a lipid bilayer) is unclear. − There has been an attempt to resolve this via the use of Comp ePhys simulations to predict ionic conductances (see next section) for comparison with experimental single-channel measurements. However, the results of this comparison and their interpretation have proved to be somewhat controversial and are the subject of an ongoing discussion. , …”

Section: Annotating New Structures: Three Recent Case Studiesmentioning

confidence: 99%

“…However, the results of this comparison and their interpretation have proved to be somewhat controversial and are the subject of an ongoing discussion. 82,83 More recently, cryo-EM has been used to determine multiple structures of the GlyR in lipid nanodiscs, which are believed to provide an environment more closely resembling the lipid bilayer in a native cell membrane. 84,85 In both studies, MD simulations were used to aid identification of a physiologically open state.…”

Section: Hydrophobic Gating In Plgic Ion Channelsmentioning

confidence: 99%

Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

et al. 2021

View full text Add to dashboard Cite

Ion channels are proteins which form gated nanopores in biological membranes. Many channels exhibit hydrophobic gating, whereby functional closure of a pore occurs by local dewetting. The pentameric ligand gated ion channels (pLGICs) provide a biologically important example of hydrophobic gating. Molecular simulation studies comparing additive vs polarizable models indicate predictions of hydrophobic gating are robust to the model employed. However, polarizable models suggest favorable interactions of hydrophobic pore-lining regions with chloride ions, of relevance to both synthetic carriers and channel proteins. Electrowetting of a closed pLGIC hydrophobic gate requires too high a voltage to occur physiologically but may inform designs for switchable nanopores. Global analysis of ∼200 channels yields a simple heuristic for structure-based prediction of (closed) hydrophobic gates. Simulation-based analysis is shown to provide an aid to interpretation of functional states of new channel structures. These studies indicate the importance of understanding the behavior of water and ions within the nanoconfined environment presented by ion channels.

show abstract

“…Among Cys-loop receptors, strychnine-sensitive GlyR, the major inhibitory ionotropic receptor in the brainstem and spinal cord, has become by far the better characterized ( Howard, 2021 ): there are over 40 structures deposited in the Protein Data Bank, mostly in open, closed and desensitized-like states ( Du et al, 2015 ; Huang et al, 2015 , 2017b , 2017a ; Kumar et al, 2020 ; Yu J. et al, 2021 , Yu et al, 2021 H. ); a few are trapped in a super-open states, whose physiological significance has been questioned, specially by MD ( Cerdan et al, 2018 ; Cerdan and Cecchini, 2020 ; Dämgen and Biggin, 2020 ; Dämgen et al, 2020 ). Apart from these rich structural data, GlyR stands out among the eukaryotic PLGICs due to its role in neurological diseases and particularly in a rare Mendelian condition known as hyperekplexia (HPX) or “startle disease” ( Lynch et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations

Mhashal

Yoluk

Orellana

2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

Pentameric ligand-gated ion channels (PLGICs) are a family of proteins that convert chemical signals into ion fluxes through cellular membranes. Their structures are highly conserved across all kingdoms from bacteria to eukaryotes. Beyond their classical roles in neurotransmission and neurological disorders, PLGICs have been recently related to cell proliferation and cancer. Here, we focus on the best characterized eukaryotic channel, the glycine receptor (GlyR), to investigate its mutational patterns in genomic-wide tumor screens and compare them with mutations linked to hyperekplexia (HPX), a Mendelian neuromotor disease that disrupts glycinergic currents. Our analysis highlights that cancer mutations significantly accumulate across TM1 and TM2, partially overlapping with HPX changes. Based on 3D-clustering, conservation, and phenotypic data, we select three mutations near the pore, expected to impact GlyR conformation, for further study by molecular dynamics (MD). Using principal components from experimental GlyR ensembles as framework, we explore the motions involved in transitions from the human closed and desensitized structures and how they are perturbed by mutations. Our MD simulations show that WT GlyR spontaneously explores opening and re-sensitization transitions that are significantly impaired by mutations, resulting in receptors with altered permeability and desensitization properties in agreement with HPX functional data.

show abstract

On the Functional Annotation of Open-Channel Structures in the Glycine Receptor

Cited by 11 publications

References 37 publications

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions

Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations

Contact Info

Product

Resources

About