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Structural Research of Cys-Loop Receptor Family

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Ligand-gated ion channels (LGICs) of the Cys-loop receptor family are composed of nicotinic acetylcholine, GABAA, GABAA-ρ, glycine, 5-HT3 receptors, and zinc-activated (ZAC) receptors. These ion channels are involved in neurotransmission and are targets for many drugs, including anesthetics, sedatives, and muscle relaxants. These receptors are pentameric, meaning they consist of five protein subunits that form a pentameric arrangement around a central pore.

In recent years, there has been significant progress in the structural research of the Cys-loop receptor family. Researchers have utilized a variety of techniques, including X-ray crystallography, cryo-electron microscopy (cryo-EM), and molecular dynamics simulations, to better understand the receptor's structure and function. X-ray crystallography has been used to determine the structures of acetylcholine receptor and the glycine receptor. These structures have provided insights into the architecture of the receptor, including the arrangement of subunits and the location of key amino acid residues involved in ligand binding and channel gating. The cryo-EM technique has enabled researchers to study the receptor in different conformations and to visualize the dynamics of the receptor's movement during ion channel gating. Molecular dynamics simulations have been used to study the behavior of these proteins in lipid bilayers and to provide insights into the receptor's interaction with its environment. These simulations have also been used to predict the effect of mutations on the receptor's function and to design novel ligands that can target specific regions of the receptor.

Landscape of differential GABAA receptor assembliesFigure 1. Landscape of differential GABAA receptor assemblies. (Sente A, et al., 2022)

ProteinOrganismMethodResolutionPDB Entry ID
Nicotinic Acetylcholine Receptor Pore (closed state)Torpedo marmorataElectron diffraction4.00 Å1OED
Nicotinic Acetylcholine Receptor, refined structureTorpedo marmorataElectron diffraction4.00 Å2BG9
Acetylcholine receptor analyzed by time-resolved electron cryo-microscopy (closed class)Torpedo marmorataTime-resolved electron cryo-microscopy6.20 Å4AQ5
Acetylcholine (ACh) receptor in complex with alpha-bungarotoxin in nanodiscsTetronarce californicaCryo-EM single particle analysis2.69 Å6UWZ
Acetylcholine (ACh) receptor, apo formTetronarce californicaCryo-EM single particle analysis2.50 Å7SMM
Nicotinic acetylcholine (ACh) receptor, resting conformationTetronarce californicaCryo-EM single particle analysis2.90 Å7QKO
Acetylcholine (ACh) receptor in complex with alpha-neurotoxin in nanodiscs (expressed in E. coli)Tetronarce californicaCryo-EM single particle analysis3.15 Å7Z14
Nicotinic Acetylcholine α4β2 Receptor (expressed in HEK293S)Homo sapiensX-ray diffraction3.94 Å5KXI
Nicotinic Acetylcholine α4β2 Receptor, 2α3β stiochiometry (expressed in HEK cells)Homo sapiensCryo-EM single particle analysis3.70 Å6CNJ
Nicotinic Acetylcholine α3β4 Receptor (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.34 Å6PV7
Nicotinic Acetylcholine α4β2 Receptor with varenicline in complex with anti-BRIL synthetic antibody BAK5 (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.87 Å6USF
Prokaryotic pentameric ligand-gated ion channel (ELIC) (expressed in E. coli)Dickeya chrysanthemiX-ray diffraction3.30 Å2VL0
Prokaryotic pentameric ligand-gated ion channel (ELIC) in complex with acetylcholine (expressed in E. coli)Dickeya dadantiiX-ray diffraction2.91 Å3RQW
Prokaryotic pentameric ligand-gated ion channel (ELIC) in complex with bromoform (expressed in E. coli)Dickeya chrysanthemiX-ray diffraction3.65 Å3ZKR
Prokaryotic pentameric ligand-gated ion channel (ELIC) in complex with Br-memantine (expressed in E. coli)Dickeya chrysanthemiX-ray diffraction3.20 Å4TWD
Prokaryotic pentameric ligand-gated ion channel, 7'C pore mutant (L238C) (expressed in E. coli)Dickeya chrysanthemiX-ray diffraction2.50 Å6HJX
Prokaryotic pentameric ligand-gated ion channel (ELIC) in POPC-only nanodiscs (expressed in E. coli)Dickeya dadantiiCryo-EM single particle analysis4.10 Å6V0B
Prokaryotic pentameric ligand-gated ion channel (ELIC) with PAM nanobody (expressed in E. coli)Dickeya chrysanthemiX-ray diffraction2.59 Å6SSI
Prokaryotic pentameric ligand-gated ion channel (GLIC) (expressed in E. coli)Gloeobacter violaceusX-ray diffraction3.10 Å3EHZ
Prokaryotic pentameric ligand-gated ion channel (GLIC) (expressed in E. coli)Gloeobacter violaceusX-ray diffraction2.90 Å3EAM
Prokaryotic pentameric ligand-gated ion channel (GLIC), wildtype-TBSb complex (expressed in E. coli)Gloeobacter violaceusX-ray diffraction3.70 Å2XQA
Prokaryotic pentameric ligand-gated ion channel (GLIC) (expressed in E. coli)Gloeobacter violaceusX-ray diffraction2.40 Å4HFI
Prokaryotic "pentameric" ligand-gated ion channel (GLIC) with hexameric quaternary structure (expressed in E. coli)Gloeobacter violaceusX-ray diffraction2.30 Å3IGQ
Prokaryotic pentameric ligand-gated ion channel (GLIC) in complex with propofol anesthetic (expressed in E. coli)Gloeobacter violaceusX-ray diffraction3.30 Å3P50
Prokaryotic pentameric ligand-gated ion channel (GLIC) in complex with ketamine anesthetic (expressed in E. coli)Gloeobacter violaceusX-ray diffraction2.99 Å4F8H
Prokaryotic pentameric ligand-gated ion channel (GLIC), pH 4 (expressed in Drosophila melanogaster)Gloeobacter violaceusX-ray diffraction3.35 Å4NPP
Prokaryotic pentameric ligand-gated ion channel (GLIC) (expressed in E. coli)Gloeobacter violaceusX-ray diffraction3.00 Å4QH5
Prokaryotic pentameric ligand-gated ion channel (GLIC), Bromoform bound, K33C-L246C mutant (expressed in E. coli)Gloeobacter violaceusX-ray diffraction2.95 Å5HCJ
Prokaryotic pentameric ligand-gated ion channel (GLIC) with bound thiopental (expressed in E. coli)Gloeobacter violaceusX-ray diffraction3.50 Å5L4E
Prokaryotic pentameric ligand-gated ion channel (GLIC) in complex with DHA (expressed in E. coli)Gloeobacter violaceusX-ray diffraction3.25 Å5J0Z
Prokaryotic pentameric ligand-gated ion channel (GLIC), open channel-stabilized mutant G-2'I + I9'A (expressed in E. coli)Gloeobacter violaceusX-ray diffraction3.12 Å5V6O
Prokaryotic pentameric ligand-gated ion channel (GLIC), H235Q apo mutant (expressed in E. coli)Gloeobacter violaceusX-ray diffraction2.95 Å5NJY
Pentameric ligand-gated ion channel (GLIC), wild-type (expressed in E. coli)Gloeobacter violaceusX-ray diffraction2.22 Å6HZW
Prokaryotic pentameric ligand-gated ion channel (GLIC), pH 7 (expressed in E. coli)Gloeobacter violaceusCryo-EM single particle analysis4.10 Å6ZGD
Prokaryotic pentameric ligand-gated ion channel (ELIC) in POPC nanodisc (expressed in E. coli)Dickeya dadantiiCryo-EM single particle analysis3.14 Å8D63
Prokaryotic pentameric ligand-gated ion channel (pLGIC) with additional N-terminal domain, closed pore (expressed in E. coli)DesulfofustisX-ray diffraction3.55 Å6V4S
Prokaryotic pentameric ligand-gated ion channel (sTeLIC), wild-type (expressed in E. coli)endosymbiont of Tevnia jerichonanaX-ray diffraction2.30 Å6FL9
Human glycine receptor (hGlyR-α1) transmembrane domain monomer (expressed in E. coli)Homo sapiensSolution NMR/2M6B
Human glycine receptor (hGlyR-α3) in complex with strychnine (expressed in Spodoptera frugiperda)Homo sapiensX-ray diffraction3.04 Å5CFB
Human glycine receptor (hGlyR-α3) N38Q mutant in complex with AM-3607 (expressed in Spodoptera frugiperda)Homo sapiensX-ray diffraction2.61 Å5TIN
Human glycine receptor (hGlyR-α3) in complex with Gly and ivermectin (expressed in Spodoptera frugiperda)Homo sapiensX-ray diffraction2.85 Å5VDH
alpha-1 GlyR Glycine receptor in complex with strychnine (expressed in Spodoptera frugiperda)Danio rerioCryo-EM single particle analysis3.90 Å3JAD
alpha-1 GlyR Glycine receptor, full-length in nanodiscs. Apo/Resting conformation (expressed in Spodoptera frugiperda)Danio rerioCryo-EM single particle analysis3.33 Å6UBS
alpha-1 glycine receptor bound with glycine in nanodisc, desensitized state (expressed in Spodoptera frugiperda)Danio rerioCryo-EM single particle analysis3.20 Å6PLR
Full length alpha1 Glycine receptor in presence of 32uM Tetrahydrocannabinol (expressed in Spodoptera frugiperda)Danio rerioCryo-EM single particle analysis3.09 Å7M6M
Glutamate-gated chloride channel (GluCl) in complex with Fab and ivermectin (expressed in Spodoptera frugiperda)Caenorhabditis elegansX-ray diffraction3.26 Å3RHW
alpha7 nAChR transmembrane domain (expressed in E. coli)Homo sapiensSolution NMR/2MAW
alpha-7 nicotinic acetylcholine receptor bound to alpha-bungarotoxin in a resting state (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.00 Å7KOO
alpha 7 nicotinic acetylcholine receptor in apo-form (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.18 Å7EKI
alpha7 neuronal ACh receptor, intracellular domain with transmembrane domain (expressed in E. coli)Homo sapiensSolution NMR/7RPM
GABAA receptor (β3 homopentamer) (expressed in HEK293F cells)Homo sapiensX-ray diffraction2.97 Å4COF
GABAA receptor (α1β2γ2) in complex with GABA and flumazenil antagonist (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.92 Å6D6U
GABAA receptor (α1β2γ2) in complex with bicuculline methbromide (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.12 Å6X3S
GABAA receptor (α1β2γ2) in complex with zolpidem (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis2.90 Å8DD2
GABAA receptor (α1β3γ2L) in nanodiscs (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.20 Å6I53
GABAA receptor (α1β3γ2L) in complex with picrotoxin (expressed in HEK293S cells)Homo sapiensCryo-EM single particle analysis3.10 Å6HUG
GABAA receptor (β3 homopentamer) in complex with histamine and megabody Mb25 in lipid nanodisc (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis1.70 Å7A5V
GABAA receptor (β3 homopentamer) in complex with histamine and megabody Mb25 (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis2.49 Å6QFA
GABAA receptor (αββαβ) with bound α-Cobratoxin (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.00 Å7PC0
GABAA receptor (α4β3δ), apo (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis2.50 Å7QN5
GABAA receptor in complex with autoimmune antibody Fab175 (expressed in HEK293 cells)Homo sapiensCryo-EM single particle analysis3.00 Å7T0Z
Benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABAA receptor (expressed in TSA201 cells)Rattus norvegicusCryo-EM single particle analysis3.80 Å6DW0
Serotonin 5-HT3A receptor (expressed in HEK293F cells)Mus musculusX-ray diffraction3.50 Å4PIR
Serotonin 5-HT3A receptor (expressed in Spodoptera frugiperda)Mus musculusCryo-EM single particle analysis4.31 Å6BE1
Serotonin 5-HT3A receptor with bound serotonin, F conformation (expressed in HEK293 cells)Mus musculusCryo-EM single particle analysis4.10 Å6HIN
Serotonin 5-HT3A receptor with bound serotonin, State 1 (expressed in Spodoptera frugiperda)Mus musculusCryo-EM single particle analysis3.32 Å6DG7
Serotonin 5-HT3A receptor with bound granisetron (expressed in Spodoptera frugiperda)Mus musculusCryo-EM single particle analysis2.92 Å6NP0
Serotonin 5-HT3A receptor in complex with palonosetron (expressed in HEK293 cells)Mus musculusCryo-EM single particle analysis2.82 Å6Y1Z
Serotonin 5-HT3A receptor in presence of Palonosetron (expressed in Spodoptera frugiperda)Mus musculusCryo-EM single particle analysis3.35 Å6W1Y
Serotonin 5-HT3A receptor with bound serotonin in Salipro bilayer discs (expressed in HEK293 cells)Mus musculusCryo-EM single particle analysis2.80 Å6Y5A

Table 1. Structural Research of Cys-Loop Receptor Family.

At Creative Biostructure, we take great pride in offering a comprehensive suite of cutting-edge protein structural analysis services that can aid in the research of the Cys-loop receptor family. Our X-ray crystallography services can determine the high-resolution structure of the receptor, while our cryo-EM services can provide structures of the receptor in different conformations.

Our team of scientists imbued with an almost unparalleled wealth of experience and a relentless commitment to excellence, is passionately dedicated to delivering outstanding results that surpass even the most exacting of client expectations. We harness the most advanced equipment and techniques to painstakingly ensure that our results are both accurate and highly reliable. With our extensive expertise in the field of protein structural analysis, honed over countless years of unparalleled success in the study of membrane proteins, we stand ready to offer our clients valuable insights into the intricacies of the structure and function of the Cys-loop receptor family, thereby opening a veritable treasure trove of new avenues for innovative and groundbreaking research. Contact us to learn more about our services and how we can assist with your research.

References

  1. Rahman M M, et al. Structure of the native muscle-type nicotinic receptor and inhibition by snake venom toxins. Neuron. 2020, 106(6): 952-962. e5.
  2. Zhang Y, et al. Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers. Nature Communications. 2021, 12(1): 1074.
  3. Sente A, et al. Differential assembly diversifies GABAA receptor structures and signalling. Nature. 2022, 604(7904): 190-194.

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