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- EMDB-20822: Human metabotropic GABA(B) receptor bound to agonist SKF97541 and... -

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Basic information

Entry
Database: EMDB / ID: EMD-20822
TitleHuman metabotropic GABA(B) receptor bound to agonist SKF97541 and positive allosteric modulator GS39783.
Map dataSharpened map of GABAB heterodimer in complex with agonist (SKF97541) and PAM (GS39783).
Sample
  • Complex: GABA(B) receptor bound to agonist and PAM
    • Protein or peptide: Gamma-aminobutyric acid type B receptor subunit 1
    • Protein or peptide: Gamma-aminobutyric acid type B receptor subunit 2
  • Ligand: (R)-(3-aminopropyl)methylphosphinic acid
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: N~4~,N~6~-dicyclopentyl-2-(methylsulfanyl)-5-nitropyrimidine-4,6-diamine
KeywordsG protein-coupled receptor / GABA / GABAB / PAM / Neurotransmitter / 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 / positive regulation of glutamate secretion / Class C/3 (Metabotropic glutamate/pheromone receptors) / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / 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
Gamma-aminobutyric acid type B receptor subunit 2 / Gamma-aminobutyric acid type B receptor subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.63 Å
AuthorsShaye H / Han GW
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM127086 United States
Department of Energy (DOE, United States)DE-AC02-76SF00515 United States
CitationJournal: Nature / Year: 2020
Title: Structural basis of the activation of a metabotropic GABA receptor.
Authors: Hamidreza Shaye / Andrii Ishchenko / Jordy Homing Lam / Gye Won Han / Li Xue / Philippe Rondard / Jean-Philippe Pin / Vsevolod Katritch / Cornelius Gati / Vadim Cherezov /
Abstract: Metabotropic γ-aminobutyric acid receptors (GABA) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that ...Metabotropic γ-aminobutyric acid receptors (GABA) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis. GABA belongs to class C of the G-protein-coupled receptors, and its functional entity comprises an obligate heterodimer that is composed of the GB1 and GB2 subunits. Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. Here we present four cryo-electron microscopy structures of the human full-length GB1-GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABA. Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signalling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface.
History
DepositionOct 14, 2019-
Header (metadata) releaseNov 27, 2019-
Map releaseJun 10, 2020-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.5
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  • Surface view with fitted model
  • Atomic models: PDB-6uo8
  • Surface level: 0.5
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20822.png

Downloads & links

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Map

FileDownload / File: emd_20822.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map of GABAB heterodimer in complex with agonist (SKF97541) and PAM (GS39783).
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 330 pix.
= 281.193 Å		0.85 Å/pix.
x 330 pix.
= 281.193 Å		0.85 Å/pix.
x 330 pix.
= 281.193 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8521 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6 / Movie #1: 0.5
Minimum - Maximum-1.0911455 - 2.7500198
Average (Standard dev.)-0.00353969 (±0.06560288)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 281.193 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.85210.85210.8521
M x/y/z330330330
origin x/y/z0.0000.0000.000
length x/y/z281.193281.193281.193
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ180180180
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS330330330
D min/max/mean-1.0912.750-0.004

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Supplemental data

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Additional map: Unfiltered map of GABAB heterodimer in complex with...

Fileemd_20822_additional.map
AnnotationUnfiltered map of GABAB heterodimer in complex with agonist (SKF97541) and PAM (GS39783).
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : GABA(B) receptor bound to agonist and PAM

EntireName: GABA(B) receptor bound to agonist and PAM
Components
  • Complex: GABA(B) receptor bound to agonist and PAM
    • Protein or peptide: Gamma-aminobutyric acid type B receptor subunit 1
    • Protein or peptide: Gamma-aminobutyric acid type B receptor subunit 2
  • Ligand: (R)-(3-aminopropyl)methylphosphinic acid
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: N~4~,N~6~-dicyclopentyl-2-(methylsulfanyl)-5-nitropyrimidine-4,6-diamine

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Supramolecule #1: GABA(B) receptor bound to agonist and PAM

SupramoleculeName: GABA(B) receptor bound to agonist and PAM / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human) / Location in cell: Membrane
Molecular weightTheoretical: 174 KDa

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Macromolecule #1: Gamma-aminobutyric acid type B receptor subunit 1

MacromoleculeName: Gamma-aminobutyric acid type B receptor subunit 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 86.450977 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GSERRAVYIG ALFPMSGGWP GGQACQPAVE MALEDVNSRR DILPDYELKL IHHDSKCDPG QATKYLYELL YNDPIKIILM PGCSSVSTL VAEAARMWNL IVLSYGSSSP ALSNRQRFPT FFRTHPSATL HNPTRVKLFE KWGWKKIATI QQTTEVFTST L DDLEERVK ...String:
GSERRAVYIG ALFPMSGGWP GGQACQPAVE MALEDVNSRR DILPDYELKL IHHDSKCDPG QATKYLYELL YNDPIKIILM PGCSSVSTL VAEAARMWNL IVLSYGSSSP ALSNRQRFPT FFRTHPSATL HNPTRVKLFE KWGWKKIATI QQTTEVFTST L DDLEERVK EAGIEITFRQ SFFSDPAVPV KNLKRQDARI IVGLFYETEA RKVFCEVYKE RLFGKKYVWF LIGWYADNWF KI YDPSINC TVDEMTEAVE GHITTEIVML NPANTRSISN MTSQEFVEKL TKRLKRHPEE TGGFQEAPLA YDAIWALALA LNK TSGGGG RSGVRLEDFN YNNQTITDQI YRAMNSSSFE GVSGHVVFDA SGSRMAWTLI EQLQGGSYKK IGYYDSTKDD LSWS KTDKW IGGSPPADQT LVIKTFRFLS QKLFISVSVL SSLGIVLAVV CLSFNIYNSH VRYIQNSQPN LNNLTAVGCS LALAA VFPL GLDGYHIGRN QFPFVCQARL WLLGLGFSLG YGSMFTKIWW VHTVFTKKEE KKEWRKTLEP WKLYATVGLL VGMDVL TLA IWQIVDPLHR TIETFAKEEP KEDIDVSILP QLEHCSSRKM NTWLGIFYGY KGLLLLLGIF LAYETKSVST EKINDHR AV GMAIYNVAVL CLITAPVTMI LSSQQDAAFA FASLAIVFSS YITLVVLFVP KMRRLITRGE WQSEAQDTMK TGSSTNNN E EEKSRLLEKE NRELEKIIAE KEERVSELRH QLQSRLEVLF Q

UniProtKB: Gamma-aminobutyric acid type B receptor subunit 1

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Macromolecule #2: Gamma-aminobutyric acid type B receptor subunit 2

MacromoleculeName: Gamma-aminobutyric acid type B receptor subunit 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 88.200844 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GWARGAPRPP PSSPPLSIMG LMPLTKEVAK GSIGRGVLPA VELAIEQIRN ESLLRPYFLD LRLYDTECDN AKGLKAFYDA IKYGPNHLM VFGGVCPSVT SIIAESLQGW NLVQLSFAAT TPVLADKKKY PYFFRTVPSD NAVNPAILKL LKHYQWKRVG T LTQDVQRF ...String:
GWARGAPRPP PSSPPLSIMG LMPLTKEVAK GSIGRGVLPA VELAIEQIRN ESLLRPYFLD LRLYDTECDN AKGLKAFYDA IKYGPNHLM VFGGVCPSVT SIIAESLQGW NLVQLSFAAT TPVLADKKKY PYFFRTVPSD NAVNPAILKL LKHYQWKRVG T LTQDVQRF SEVRNDLTGV LYGEDIEISD TESFSNDPCT SVKKLKGNDV RIILGQFDQN MAAKVFCCAY EENMYGSKYQ WI IPGWYEP SWWEQVHTEA NSSRCLRKNL LAAMEGYIGV DFEPLSSKQI KTISGKTPQQ YEREYNNKRS GVGPSKFHGY AYD GIWVIA KTLQRAMETL HASSRHQRIQ DFNYTDHTLG RIILNAMNET NFFGVTGQVV FRNGERMGTI KFTQFQDSRE VKVG EYNAV ADTLEIINDT IRFQGSEPPK DKTIILEQLR KISLPLYSIL SALTILGMIM ASAFLFFNIK NRNQKLIKMS SPYMN NLII LGGMLSYASI FLFGLDGSFV SEKTFETLCT VRTWILTVGY TTAFGAMFAK TWRVHAIFKN VKMKKKIIKD QKLLVI VGG MLLIDLCILI CWQAVDPLRR TVEKYSMEPD PAGRDISIRP LLEHCENTHM TIWLGIVYAY KGLLMLFGCF LAWETRN VS IPALNDSKYI GMSVYNVGIM CIIGAAVSFL TRDQPNVQFC IVALVIIFCS TITLCLVFVP KLITLRTNPD AATQNRRF Q FTQNQKKEDS KTSTSVTSVN QASTSRLEGL QSENHRLRMK ITELDKDLEE VTMQLQDT

UniProtKB: Gamma-aminobutyric acid type B receptor subunit 2

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Macromolecule #5: (R)-(3-aminopropyl)methylphosphinic acid

MacromoleculeName: (R)-(3-aminopropyl)methylphosphinic acid / type: ligand / ID: 5 / Number of copies: 1 / Formula: QD7
Molecular weightTheoretical: 137.117 Da
Chemical component information

ChemComp-QD7:
(R)-(3-aminopropyl)methylphosphinic acid / agonist*YM

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #7: N~4~,N~6~-dicyclopentyl-2-(methylsulfanyl)-5-nitropyrimidine-4,6-...

MacromoleculeName: N~4~,N~6~-dicyclopentyl-2-(methylsulfanyl)-5-nitropyrimidine-4,6-diamine
type: ligand / ID: 7 / Number of copies: 1 / Formula: QDA
Molecular weightTheoretical: 337.44 Da
Chemical component information

ChemComp-QDA:
N~4~,N~6~-dicyclopentyl-2-(methylsulfanyl)-5-nitropyrimidine-4,6-diamine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration10 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 40 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 293.15 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 10917 / Average exposure time: 0.07 sec. / Average electron dose: 1.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 29000 / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: -3.0 µm / Nominal defocus min: -1.5 µm / Nominal magnification: 29000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4173286
Startup modelType of model: OTHER / Details: Initial model generation in cryoSPARC.
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.63 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.12.14) / Number images used: 89001
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.12.14)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.12.14)
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC (ver. 2.12.14)

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Atomic model buiding 1

Initial model
PDB IDChain

4ms3

source_name: PDB, initial_model_type: experimental model

4or2

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-6uo8:
Human metabotropic GABA(B) receptor bound to agonist SKF97541 and positive allosteric modulator GS39783

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