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- EMDB-25126: Cryo-EM structure of GPR158 coupled to the RGS7-Gbeta5 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-25126
TitleCryo-EM structure of GPR158 coupled to the RGS7-Gbeta5 complex
Map data
Sample
  • Complex: GPCR complexG protein-coupled receptor
    • Protein or peptide: Isoform 2 of Regulator of G-protein signaling 7
    • Protein or peptide: Guanine nucleotide-binding protein subunit beta-5
    • Protein or peptide: G-protein coupled receptor 158
  • Ligand: CHOLESTEROL
  • Ligand: (2S)-1-{[(S)-hydroxy{[(1s,2R,3R,4R,5S,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl (5E,8E,11E,14E)-icosa-5,8,11,14-tetraenoate
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine
Function / homology
Function and homology information


G protein-coupled glycine receptor activity / Inactivation, recovery and regulation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK ...G protein-coupled glycine receptor activity / Inactivation, recovery and regulation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / light adaption / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / dark adaptation / Thromboxane signalling through TP receptor / G-protein gamma-subunit binding / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Ca2+ pathway / G alpha (s) signalling events / G alpha (q) signalling events / Extra-nuclear estrogen signaling / negative regulation of voltage-gated calcium channel activity / G alpha (12/13) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (i) signalling events / GPER1 signaling / negative regulation of G protein-coupled receptor signaling pathway / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / positive regulation of potassium ion transmembrane transport / ADP signalling through P2Y purinoceptor 1 / regulation of G protein-coupled receptor signaling pathway / positive regulation of neurotransmitter secretion / GTPase activating protein binding / dopamine receptor signaling pathway / regulation of synapse organization / enzyme activator activity / G-protein alpha-subunit binding / response to amphetamine / GTPase activator activity / cell projection / G protein-coupled receptor activity / protein localization to plasma membrane / brain development / cognition / positive regulation of GTPase activity / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / transmembrane signaling receptor activity / presynapse / presynaptic membrane / myelin sheath / nuclear envelope / cell body / G alpha (i) signalling events / protein-folding chaperone binding / postsynaptic membrane / response to ethanol / neuron projection / intracellular signal transduction / G protein-coupled receptor signaling pathway / GTPase activity / protein-containing complex / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / : / G-protein coupled receptor 158/179 / Regulator of G-protein signalling, DHEX domain / Regulator of G-protein signalling DHEX domain / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / Regulator of G protein signaling domain ...: / : / G-protein coupled receptor 158/179 / Regulator of G-protein signalling, DHEX domain / Regulator of G-protein signalling DHEX domain / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / Regulator of G protein signaling domain / RGS, subdomain 2 / RGS domain / RGS domain profile. / Regulator of G protein signalling domain / RGS domain superfamily / GPCR family 3, C-terminal / 7 transmembrane sweet-taste receptor of 3 GCPR / G-protein coupled receptors family 3 profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / Winged helix DNA-binding domain superfamily / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / Winged helix-like DNA-binding domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Regulator of G-protein signaling 7 / Guanine nucleotide-binding protein subunit beta-5 / Metabotropic glycine receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsPatil DN / Singh S / Singh AK / Martemyanov KA
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Mental Health (NIH/NIMH) United States
CitationJournal: Science / Year: 2022
Title: Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gβ5 signaling complex.
Authors: Dipak N Patil / Shikha Singh / Thibaut Laboute / Timothy S Strutzenberg / Xingyu Qiu / Di Wu / Scott J Novick / Carol V Robinson / Patrick R Griffin / John F Hunt / Tina Izard / Appu K Singh ...Authors: Dipak N Patil / Shikha Singh / Thibaut Laboute / Timothy S Strutzenberg / Xingyu Qiu / Di Wu / Scott J Novick / Carol V Robinson / Patrick R Griffin / John F Hunt / Tina Izard / Appu K Singh / Kirill A Martemyanov /
Abstract: GPR158 is an orphan G protein–coupled receptor (GPCR) highly expressed in the brain, where it controls synapse formation and function. GPR158 has also been implicated in depression, carcinogenesis, ...GPR158 is an orphan G protein–coupled receptor (GPCR) highly expressed in the brain, where it controls synapse formation and function. GPR158 has also been implicated in depression, carcinogenesis, and cognition. However, the structural organization and signaling mechanisms of GPR158 are largely unknown. We used single-particle cryo–electron microscopy (cryo-EM) to determine the structures of human GPR158 alone and bound to an RGS signaling complex. The structures reveal a homodimeric organization stabilized by a pair of phospholipids and the presence of an extracellular Cache domain, an unusual ligand-binding domain in GPCRs. We further demonstrate the structural basis of GPR158 coupling to RGS7-Gβ5. Together, these results provide insights into the unusual biology of orphan receptors and the formation of GPCR-RGS complexes.
History
DepositionOct 8, 2021-
Header (metadata) releaseDec 1, 2021-
Map releaseDec 1, 2021-
UpdateJan 19, 2022-
Current statusJan 19, 2022Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.359
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.359
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7shf
  • Surface level: 0.359
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_25126.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.873 Å
Density
Contour LevelBy AUTHOR: 0.359 / Movie #1: 0.359
Minimum - Maximum-2.1638293 - 3.3204675
Average (Standard dev.)0.0007287576 (±0.054183245)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 349.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8730.8730.873
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z349.200349.200349.200
α/β/γ90.00090.00090.000
start NX/NY/NZ-140-140-140
NX/NY/NZ280280280
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-2.1643.3200.001

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Supplemental data

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Sample components

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Entire : GPCR complex

EntireName: GPCR complexG protein-coupled receptor
Components
  • Complex: GPCR complexG protein-coupled receptor
    • Protein or peptide: Isoform 2 of Regulator of G-protein signaling 7
    • Protein or peptide: Guanine nucleotide-binding protein subunit beta-5
    • Protein or peptide: G-protein coupled receptor 158
  • Ligand: CHOLESTEROL
  • Ligand: (2S)-1-{[(S)-hydroxy{[(1s,2R,3R,4R,5S,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl (5E,8E,11E,14E)-icosa-5,8,11,14-tetraenoate
  • Ligand: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

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Supramolecule #1: GPCR complex

SupramoleculeName: GPCR complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 270 KDa

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Macromolecule #1: Isoform 2 of Regulator of G-protein signaling 7

MacromoleculeName: Isoform 2 of Regulator of G-protein signaling 7 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.761859 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAQGNNYGQT SNGVADESPN MLVYRKMEDV IARMQDEKNG IPIRTVKSFL SKIPSVFSGS DIVQWLIKNL TIEDPVEALH LGTLMAAHG YFFPISDHVL TLKDDGTFYR FQTPYFWPSN CWEPENTDYA VYLCKRTMQN KARLELADYE AESLARLQRA F ARKWEFIF ...String:
MAQGNNYGQT SNGVADESPN MLVYRKMEDV IARMQDEKNG IPIRTVKSFL SKIPSVFSGS DIVQWLIKNL TIEDPVEALH LGTLMAAHG YFFPISDHVL TLKDDGTFYR FQTPYFWPSN CWEPENTDYA VYLCKRTMQN KARLELADYE AESLARLQRA F ARKWEFIF MQAEAQAKVD KKRDKIERKI LDSQERAFWD VHRPVPGCVN TTEVDIKKSS RMRNPHKTRK SVYGLQNDIR SH SPTHTPT PETKPPTEDE LQQQIKYWQI QLDRHRLKMS KVADSLLSYT EQYLEYDPFL LPPDPSNPWL SDDTTFWELE ASK EPSQQR VKRWGFGMDE ALKDPVGREQ FLKFLESEFS SENLRFWLAV EDLKKRPIKE VPSRVQEIWQ EFLAPGAPSA INLD SKSYD KTTQNVKEPG RYTFEDAQEH IYKLMKSDSY PRFIRSSAYQ ELLQAKKKGK SLTSKRLTSL AQSY

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Macromolecule #2: Guanine nucleotide-binding protein subunit beta-5

MacromoleculeName: Guanine nucleotide-binding protein subunit beta-5 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 38.778602 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATDGLHENE TLASLKSEAE SLKGKLEEER AKLHDVELHQ VAERVEALGQ FVMKTRRTLK GHGNKVLCMD WCKDKRRIVS SSQDGKVIV WDSFTTNKEH AVTMPCTWVM ACAYAPSGCA IACGGLDNKC SVYPLTFDKN ENMAAKKKSV AMHTNYLSAC S FTNSDMQI ...String:
MATDGLHENE TLASLKSEAE SLKGKLEEER AKLHDVELHQ VAERVEALGQ FVMKTRRTLK GHGNKVLCMD WCKDKRRIVS SSQDGKVIV WDSFTTNKEH AVTMPCTWVM ACAYAPSGCA IACGGLDNKC SVYPLTFDKN ENMAAKKKSV AMHTNYLSAC S FTNSDMQI LTASGDGTCA LWDVESGQLL QSFHGHGADV LCLDLAPSET GNTFVSGGCD KKAMVWDMRS GQCVQAFETH ES DVNSVRY YPSGDAFASG SDDATCRLYD LRADREVAIY SKESIIFGAS SVDFSLSGRL LFAGYNDYTI NVWDVLKGSR VSI LFGHEN RVSTLRVSPD GTAFCSGSWD HTLRVWA

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Macromolecule #3: G-protein coupled receptor 158

MacromoleculeName: G-protein coupled receptor 158 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 88.251633 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGAMAYPLLL CLLLAQLGLG AVGASRDPQG RPDSPRERTP KGKPHAQQPG RASASDSSAP WSRSTDGTIL AQKLAEEVPM DVASYLYTG DSHQLKRANC SGRYELAGLP GKWPALASAH PSLHRALDTL THATNFLNVM LQSNKSREQN LQDDLDWYQA L VWSLLEGE ...String:
MGAMAYPLLL CLLLAQLGLG AVGASRDPQG RPDSPRERTP KGKPHAQQPG RASASDSSAP WSRSTDGTIL AQKLAEEVPM DVASYLYTG DSHQLKRANC SGRYELAGLP GKWPALASAH PSLHRALDTL THATNFLNVM LQSNKSREQN LQDDLDWYQA L VWSLLEGE PSISRAAITF STDSLSAPAP QVFLQATREE SRILLQDLSS SAPHLANATL ETEWFHGLRR KWRPHLHRRG PN QGPRGLG HSWRRKDGLG GDKSHFKWSP PYLECENGSY KPGWLVTLSS AIYGLQPNLV PEFRGVMKVD INLQKVDIDQ CSS DGWFSG THKCHLNNSE CMPIKGLGFV LGAYECICKA GFYHPGVLPV NNFRRRGPDQ HISGSTKDVS EEAYVCLPCR EGCP FCADD SPCFVQEDKY LRLAIISFQA LCMLLDFVSM LVVYHFRKAK SIRASGLILL ETILFGSLLL YFPVVILYFE PSTFR CILL RWARLLGFAT VYGTVTLKLH RVLKVFLSRT AQRIPYMTGG RVMRMLAVIL LVVFWFLIGW TSSVCQNLEK QISLIG QGK TSDHLIFNMC LIDRWDYMTA VAEFLFLLWG VYLCYAVRTV PSAFHEPRYM AVAVHNELII SAIFHTIRFV LASRLQS DW MLMLYFAHTH LTVTVTIGLL LIPKFSHSSN NPRDDIATEA YEDELDMGRS GSYLNSSINS AWSEHSLDPE DIRDELKK L YAQLEIYKRK KMITNNPHLQ KKRCSKKGLG RSIMRRITEI PETVSRQCSK EDKELEVLFQ

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 22 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #5: (2S)-1-{[(S)-hydroxy{[(1s,2R,3R,4R,5S,6S)-2,3,4,5,6-pentahydroxyc...

MacromoleculeName: (2S)-1-{[(S)-hydroxy{[(1s,2R,3R,4R,5S,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl (5E,8E,11E,14E)-icosa-5,8,11,14-tetraenoate
type: ligand / ID: 5 / Number of copies: 1 / Formula: EIJ
Molecular weightTheoretical: 887.128 Da
Chemical component information

ChemComp-EIJ:
(2S)-1-{[(S)-hydroxy{[(1s,2R,3R,4R,5S,6S)-2,3,4,5,6-pentahydroxycyclohexyl]oxy}phosphoryl]oxy}-3-(octadecanoyloxy)propan-2-yl (5E,8E,11E,14E)-icosa-5,8,11,14-tetraenoate

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Macromolecule #6: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

MacromoleculeName: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / type: ligand / ID: 6 / Number of copies: 1 / Formula: PEE
Molecular weightTheoretical: 744.034 Da
Chemical component information

ChemComp-PEE:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine / DOPE, phospholipid*YM / Discrete optimized protein energy

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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

Concentration0.3 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

Details: GPR158 model taken from ab-initio built for GPR158 apo and RGS7-Gb5 from PDB ID: 6N9G
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 151954

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