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- PDB-7cum: Cryo-EM structure of human GABA(B) receptor bound to the antagoni... -

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Basic information

Entry
Database: PDB / ID: 7cum
TitleCryo-EM structure of human GABA(B) receptor bound to the antagonist CGP54626
Components
  • Gamma-aminobutyric acid type B receptor subunit 1
  • Gamma-aminobutyric acid type B receptor subunit 2
KeywordsSIGNALING PROTEIN / GPCR / GABA / Neurosignalling / MEMBRANE PROTEIN
Function / homology
Function and homology information


G protein-coupled neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / GABA B receptor activation / G protein-coupled neurotransmitter receptor activity involved in regulation of presynaptic membrane potential / G protein-coupled GABA receptor complex / negative regulation of gamma-aminobutyric acid secretion / neuron-glial cell signaling / G protein-coupled GABA receptor activity / G protein-coupled receptor heterodimeric complex / negative regulation of epinephrine secretion / negative regulation of dopamine secretion ...G protein-coupled neurotransmitter receptor activity involved in regulation of postsynaptic membrane potential / GABA B receptor activation / G protein-coupled neurotransmitter receptor activity involved in regulation of presynaptic membrane potential / G protein-coupled GABA receptor complex / negative regulation of gamma-aminobutyric acid secretion / neuron-glial cell signaling / G protein-coupled GABA receptor activity / G protein-coupled receptor heterodimeric complex / negative regulation of epinephrine secretion / negative regulation of dopamine secretion / positive regulation of growth hormone secretion / extracellular matrix protein binding / GABA receptor complex / negative regulation of adenylate cyclase activity / Class C/3 (Metabotropic glutamate/pheromone receptors) / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / positive regulation of glutamate secretion / negative regulation of synaptic transmission / axolemma / GABA-ergic synapse / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / dendritic shaft / response to nicotine / mitochondrial membrane / Schaffer collateral - CA1 synapse / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / osteoblast differentiation / transmembrane signaling receptor activity / synaptic vesicle / presynaptic membrane / G alpha (i) signalling events / chemical synaptic transmission / postsynaptic membrane / response to ethanol / dendritic spine / neuron projection / protein heterodimerization activity / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / neuronal cell body / glutamatergic synapse / endoplasmic reticulum membrane / extracellular space / plasma membrane / cytoplasm
Similarity search - Function
GPCR family 3, gamma-aminobutyric acid receptor, type B2 / Gamma-aminobutyric acid type B receptor subunit 2, coiled-coil domain / Gamma-aminobutyric acid type B receptor subunit 2 coiled-coil domain / GPCR family 3, gamma-aminobutyric acid receptor, type B1 / GPCR family 3, GABA-B receptor / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal ...GPCR family 3, gamma-aminobutyric acid receptor, type B2 / Gamma-aminobutyric acid type B receptor subunit 2, coiled-coil domain / Gamma-aminobutyric acid type B receptor subunit 2 coiled-coil domain / GPCR family 3, gamma-aminobutyric acid receptor, type B1 / GPCR family 3, GABA-B receptor / GPCR, family 3, conserved site / G-protein coupled receptors family 3 signature 3. / GPCR, family 3 / G-protein coupled receptors family 3 profile. / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Chem-2BV / CHOLESTEROL / Unknown ligand / Gamma-aminobutyric acid type B receptor subunit 2 / Gamma-aminobutyric acid type B receptor subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.52 Å
AuthorsKim, Y. / Jeong, E. / Jeong, J. / Kim, Y. / Cho, Y.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
Other privateSamsung Science and Technology Foundation SSTF-BA1602-14 Korea, Republic Of
CitationJournal: J Mol Biol / Year: 2020
Title: Structural Basis for Activation of the Heterodimeric GABA Receptor.
Authors: Yoojoong Kim / Eunyoung Jeong / Ji-Hong Jeong / Youngjin Kim / Yunje Cho /
Abstract: The neurotransmitter γ-aminobutyric acid (GABA) activates the metabotropic GABA receptor to generate slow, prolonged inhibitory signals that regulate the neural circuitry. The GABA receptor is an ...The neurotransmitter γ-aminobutyric acid (GABA) activates the metabotropic GABA receptor to generate slow, prolonged inhibitory signals that regulate the neural circuitry. The GABA receptor is an obligate heterodimeric G protein-coupled receptor (GPCR) comprised of GBR1 and GBR2 subunits, each with extracellular, seven-helix transmembrane (7TM), and coiled-coil domains. To understand how GABA-driven conformational changes in the extracellular domain are transmitted to the 7TM domain during signal transduction, we determined cryo-electron microscopy (EM) structures of GABA in two different states: an antagonist-bound inactive state, and an active state in which both the GABA agonist and a positive allosteric modulator (PAM) are bound. In the inactive state, the TM3 and TM5 helices in the two 7TM domains engage in cholesterol-mediated as well as direct interactions, resulting in an open conformation. GABA binding forces the extracellular domains of GBR1 and GBR2 into a compact form, relocating the linkers that connect the extracellular and 7TM domains closer to each other. The movement of the linker along with the associated extracellular loop 2 of the 7TM domain reorients the two 7TM domains and creates a new interface with the TM5, TM6 and TM7 helices in a closed conformation. PAM binding to the interface between the TM6 and TM6 helices stabilizes the active 7TM domain conformation. The relayed structural rearrangement results in significant conformational changes in the TM helices, as well as intracellular loop 3 in GBR2, which may promote the binding and activation of the Gi/o proteins.
History
DepositionAug 23, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 11, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Gamma-aminobutyric acid type B receptor subunit 1
B: Gamma-aminobutyric acid type B receptor subunit 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)187,70321
Polymers179,4792
Non-polymers8,22319
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: scanning transmission electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14870 Å2
ΔGint-24 kcal/mol
Surface area65740 Å2

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Components

#1: Protein Gamma-aminobutyric acid type B receptor subunit 1 / Gb1


Mass: 87248.195 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GABBR1, GPRC3A / Production host: Homo sapiens (human) / References: UniProt: Q9UBS5
#2: Protein Gamma-aminobutyric acid type B receptor subunit 2 / Gb2 / G-protein coupled receptor 51 / HG20


Mass: 92231.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GABBR2, GPR51, GPRC3B / Production host: Homo sapiens (human) / References: UniProt: O75899
#3: Chemical ChemComp-2BV / (R)-(cyclohexylmethyl)[(2S)-3-{[(1S)-1-(3,4-dichlorophenyl)ethyl]amino}-2-hydroxypropyl]phosphinic acid / CGP 54626


Mass: 408.300 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H28Cl2NO3P / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-UNL / UNKNOWN LIGAND


Mass: 814.167 Da / Num. of mol.: 2 / Source method: obtained synthetically / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY
Nonpolymer detailsThe phospholipid-like ligands are similar to U3G and U3D respectively but not exactly same. Since ...The phospholipid-like ligands are similar to U3G and U3D respectively but not exactly same. Since they were not characterized due to the unknown part, they are assigned with UNL.

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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: Gamma-aminobutyric acid type B receptor / Type: COMPLEX
Details: Antagonist-bound Gamma-aminobutyric acid type B receptor
Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 200 kDa/nm / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: C-flat-1.2/1.3
VitrificationCryogen name: ETHANE

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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: DIFFRACTION
Image recording
IDImaging-IDElectron dose (e/Å2)Film or detector model
1150GATAN K3 (6k x 4k)
2150GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.14_3260: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.52 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 512675 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00711687
ELECTRON MICROSCOPYf_angle_d2.4815919
ELECTRON MICROSCOPYf_dihedral_angle_d9.1936738
ELECTRON MICROSCOPYf_chiral_restr0.2641843
ELECTRON MICROSCOPYf_plane_restr0.0071889

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