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- PDB-8fe1: Alpha1/BetaB Heteromeric Glycine Receptor in 1 mM Glycine 20 uM I... -

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Basic information

Entry
Database: PDB / ID: 8fe1
TitleAlpha1/BetaB Heteromeric Glycine Receptor in 1 mM Glycine 20 uM Ivermectin State
Components(Glycine receptor ...) x 2
KeywordsMEMBRANE PROTEIN / Glycine / Channel / Ivermectin / Pentameric
Function / homology
Function and homology information


Neurotransmitter receptors and postsynaptic signal transmission / extracellularly glycine-gated ion channel activity / extracellularly glycine-gated chloride channel activity / synaptic transmission, glycinergic / cellular response to ethanol / cellular response to zinc ion / neurotransmitter receptor activity / regulation of neuron differentiation / glycine binding / chloride channel complex ...Neurotransmitter receptors and postsynaptic signal transmission / extracellularly glycine-gated ion channel activity / extracellularly glycine-gated chloride channel activity / synaptic transmission, glycinergic / cellular response to ethanol / cellular response to zinc ion / neurotransmitter receptor activity / regulation of neuron differentiation / glycine binding / chloride channel complex / ligand-gated monoatomic ion channel activity / transmembrane transporter complex / neuropeptide signaling pathway / response to amino acid / monoatomic ion transport / chloride transmembrane transport / central nervous system development / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / cellular response to amino acid stimulus / protein localization / transmembrane signaling receptor activity / postsynaptic membrane / perikaryon / neuron projection / synapse / dendrite / zinc ion binding / membrane / plasma membrane
Similarity search - Function
: / Glycine receptor beta / Glycine receptor alpha1 / Glycine receptor alpha / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily ...: / Glycine receptor beta / Glycine receptor alpha1 / Glycine receptor alpha / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain
Similarity search - Domain/homology
DECANE / GLYCINE / Chem-IVM / PALMITIC ACID / 1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Glycine receptor subunit alphaZ1 / Glycine receptor beta subunit 2
Similarity search - Component
Biological speciesDanio rerio (zebrafish)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsGibbs, E. / Chakrapani, S.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1F32GM142233 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM134896 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM134896-2S1 United States
Citation
Journal: Nat Commun / Year: 2023
Title: Conformational transitions and allosteric modulation in a heteromeric glycine receptor.
Authors: Eric Gibbs / Emily Klemm / David Seiferth / Arvind Kumar / Serban L Ilca / Philip C Biggin / Sudha Chakrapani /
Abstract: Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric ...Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric assembly of α and β subunits. Here we present cryo-EM structures of full-length zebrafish α1βGlyR in the presence of an antagonist (strychnine), agonist (glycine), or agonist with a positive allosteric modulator (glycine/ivermectin). Each structure shows a distinct pore conformation with varying degrees of asymmetry. Molecular dynamic simulations found the structures were in a closed (strychnine) and desensitized states (glycine and glycine/ivermectin). Ivermectin binds at all five interfaces, but in a distinct binding pose at the β-α interface. Subunit-specific features were sufficient to solve structures without a fiduciary marker and to confirm the 4α:1β stoichiometry recently observed. We also report features of the extracellular and intracellular domains. Together, our results show distinct compositional and conformational properties of αβGlyR and provide a framework for further study of this physiologically important channel.
#1: Journal: Nat Chem Biol / Year: 2024
Title: High-throughput reprogramming of an NRPS condensation domain.
Authors: Ines B Folger / Natália F Frota / Angelos Pistofidis / David L Niquille / Douglas A Hansen / T Martin Schmeing / Donald Hilvert /
Abstract: Engineered biosynthetic assembly lines could revolutionize the sustainable production of bioactive natural product analogs. Although yeast display is a proven, powerful tool for altering the ...Engineered biosynthetic assembly lines could revolutionize the sustainable production of bioactive natural product analogs. Although yeast display is a proven, powerful tool for altering the substrate specificity of gatekeeper adenylation domains in nonribosomal peptide synthetases (NRPSs), comparable strategies for other components of these megaenzymes have not been described. Here we report a high-throughput approach for engineering condensation (C) domains responsible for peptide elongation. We show that a 120-kDa NRPS module, displayed in functional form on yeast, can productively interact with an upstream module, provided in solution, to produce amide products tethered to the yeast surface. Using this system to screen a large C-domain library, we reprogrammed a surfactin synthetase module to accept a fatty acid donor, increasing catalytic efficiency for this noncanonical substrate >40-fold. Because C domains can function as selectivity filters in NRPSs, this methodology should facilitate the precision engineering of these molecular assembly lines.
#2: Journal: Nat Commun / Year: 2023
Title: Conformational transitions and allosteric modulation in a heteromeric glycine receptor
Authors: Gibbs, E. / Klemm, E. / Seiferth, D. / Kumar, A. / Ilca, S.L. / Biggin, P.C. / Chakrapani, S.
History
DepositionDec 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 28, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Revision 1.2Jun 12, 2024Group: Database references / Category: citation / citation_author

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Glycine receptor subunit alphaZ1
D: Glycine receptor subunit alphaZ1
C: Glycine receptor subunit alphaZ1
B: Glycine receptor subunit alphaZ1
E: Glycine receptor beta subunit 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)294,80258
Polymers275,9715
Non-polymers18,83253
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Glycine receptor ... , 2 types, 5 molecules ADCBE

#1: Protein
Glycine receptor subunit alphaZ1


Mass: 52537.598 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: glra1
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: O93430
#2: Protein Glycine receptor beta subunit 2 / Glycine receptor / beta b / glycine receptor subunit beta precursor


Mass: 65820.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: glrb2, zgc:101041, glrbb, SO:0001217
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: Q6DC22

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Sugars , 1 types, 6 molecules

#4: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 5 types, 47 molecules

#3: Chemical
ChemComp-GLY / GLYCINE


Type: peptide linking / Mass: 75.067 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H5NO2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-IVM / (2aE,4E,5'S,6S,6'R,7S,8E,11R,13R,15S,17aR,20R,20aR,20bS)-6'-[(2S)-butan-2-yl]-20,20b-dihydroxy-5',6,8,19-tetramethyl-17 -oxo-3',4',5',6,6',10,11,14,15,17,17a,20,20a,20b-tetradecahydro-2H,7H-spiro[11,15-methanofuro[4,3,2-pq][2,6]benzodioxacy clooctadecine-13,2'-pyran]-7-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-alpha-L-arabino-hexopyranosyl)-3-O-methyl-alpha-L-arabino-hexopyranoside / 22,23-DIHYDROAVERMECTIN B1A / IVERMECTIN


Mass: 875.093 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C48H74O14 / Feature type: SUBJECT OF INVESTIGATION / Comment: antiparasitic*YM
#6: Chemical
ChemComp-PX4 / 1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE


Mass: 678.940 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C36H73NO8P / Comment: DMPC, phospholipid*YM
#7: Chemical...
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 28 / Source method: obtained synthetically / Formula: C16H32O2
#8: Chemical ChemComp-D10 / DECANE


Mass: 142.282 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Zebrafish Alpha1 BetaB Heteromeric Glycine Receptor / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: .25 MDa / Experimental value: NO
Source (natural)Organism: Danio rerio (zebrafish)
Source (recombinant)Organism: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium ChlorideNaCl1
220 mMHEPESC8H18N2O4S1
31 mMDodecyl-D-MaltopyranosideC24H46O111
41 mMGlycineC2H5NO21
520 uMIvermectinC48H74O141
60.1 %DMSOC2H6OS1
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Single Particles
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategoryDetails
4Gctf8CTF correction
10cryoSPARC3.3.2initial Euler assignment
11cryoSPARC3.3.2final Euler assignment
12RELION4classification
13cryoSPARC3.3.23D reconstructionNon-uniform Refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 204512 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00315781
ELECTRON MICROSCOPYf_angle_d0.73321225
ELECTRON MICROSCOPYf_dihedral_angle_d13.2622538
ELECTRON MICROSCOPYf_chiral_restr0.0482363
ELECTRON MICROSCOPYf_plane_restr0.0052575

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