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- PDB-7d77: Cryo-EM structure of the cortisol-bound adhesion receptor GPR97-G... -

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Basic information

Entry
Database: PDB / ID: 7d77
TitleCryo-EM structure of the cortisol-bound adhesion receptor GPR97-Go complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Adhesion G protein-coupled receptor G3; GPR97
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR / GPR97 / complex / adhesion G protein-coupled receptor
Function / homology
Function and homology information


negative regulation of CREB transcription factor activity / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / vesicle docking involved in exocytosis / negative regulation of non-canonical NF-kappaB signal transduction / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / negative regulation of insulin secretion / specific granule membrane / G protein-coupled serotonin receptor binding ...negative regulation of CREB transcription factor activity / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / vesicle docking involved in exocytosis / negative regulation of non-canonical NF-kappaB signal transduction / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / negative regulation of insulin secretion / specific granule membrane / G protein-coupled serotonin receptor binding / muscle contraction / regulation of cell migration / B cell differentiation / locomotory behavior / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell body / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / Neutrophil degranulation / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5 / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. ...GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5 / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / 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 / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
CHOLESTEROL / Chem-HCY / PALMITIC ACID / CHOLESTEROL HEMISUCCINATE / Guanine nucleotide-binding protein G(o) subunit alpha / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Adhesion G protein-coupled receptor G3
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsPing, Y. / Mao, C. / Xiao, P. / Zhao, R. / Jiang, Y. / Yang, Z. / An, W. / Shen, D. / Yang, F. / Zhang, H. ...Ping, Y. / Mao, C. / Xiao, P. / Zhao, R. / Jiang, Y. / Yang, Z. / An, W. / Shen, D. / Yang, F. / Zhang, H. / Qu, C. / Shen, Q. / Tian, C. / Li, Z. / Li, S. / Wang, G. / Tao, X. / Wen, X. / Zhong, Y. / Yang, J. / Yi, F. / Yu, X. / Xu, E. / Zhang, Y. / Sun, J.
CitationJournal: Nature / Year: 2021
Title: Structures of the glucocorticoid-bound adhesion receptor GPR97-G complex.
Authors: Yu-Qi Ping / Chunyou Mao / Peng Xiao / Ru-Jia Zhao / Yi Jiang / Zhao Yang / Wen-Tao An / Dan-Dan Shen / Fan Yang / Huibing Zhang / Changxiu Qu / Qingya Shen / Caiping Tian / Zi-Jian Li / ...Authors: Yu-Qi Ping / Chunyou Mao / Peng Xiao / Ru-Jia Zhao / Yi Jiang / Zhao Yang / Wen-Tao An / Dan-Dan Shen / Fan Yang / Huibing Zhang / Changxiu Qu / Qingya Shen / Caiping Tian / Zi-Jian Li / Shaolong Li / Guang-Yu Wang / Xiaona Tao / Xin Wen / Ya-Ni Zhong / Jing Yang / Fan Yi / Xiao Yu / H Eric Xu / Yan Zhang / Jin-Peng Sun /
Abstract: Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available. Here we report that glucocorticoid stress ...Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available. Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97), a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-G complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W, which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the G protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the G protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.
History
DepositionOct 3, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 3, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 10, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(o) subunit alpha
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Adhesion G protein-coupled receptor G3; GPR97
S: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)163,16312
Polymers160,7725
Non-polymers2,3927
Water181
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area14930 Å2
ΔGint-66 kcal/mol
Surface area47600 Å2

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(o) subunit alpha


Mass: 25286.922 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAO1 / Cell (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P09471*PLUS
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38245.801 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Cell (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Cell (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein / Antibody , 2 types, 2 molecules RS

#4: Protein Adhesion G protein-coupled receptor G3; GPR97


Mass: 62767.098 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADGRG3 / Cell (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q86Y34*PLUS
#5: Antibody scFv16


Mass: 26610.615 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Cell (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm)

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Non-polymers , 5 types, 8 molecules

#6: Chemical ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C16H32O2
#7: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4
#8: Chemical ChemComp-HCY / (11alpha,14beta)-11,17,21-trihydroxypregn-4-ene-3,20-dione / CORTISOL


Mass: 362.460 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30O5 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, hormone*YM
#9: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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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

Component
IDNameTypeEntity IDParent-IDSource
1Cortisol-bound adhesion receptor GPR97-Go complexCOMPLEX#1-#50RECOMBINANT
2Adhesion G protein-coupled receptor G3; GPR97COMPLEX#41RECOMBINANT
3GoCOMPLEX#1-#31RECOMBINANT
4scFv16COMPLEX#51RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
12Spodoptera frugiperda (fall armyworm)7108sf9
23Spodoptera frugiperda (fall armyworm)7108sf9
34Spodoptera frugiperda (fall armyworm)7108sf9
Buffer solutionpH: 7.5
SpecimenConc.: 20 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen 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: BRIGHT FIELD / Nominal magnification: 29000 X / Calibrated magnification: 49310 X / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 62 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 5871
Image scansMovie frames/image: 40

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
4Gctfv1.18CTF correction
7Coot0.89model fitting
9PHENIX1.16model refinement
13RELION3.0-beta23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4323518
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 75814 / Symmetry type: POINT
Atomic model buildingPDB-ID: 6G79

6g79

Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0068981
ELECTRON MICROSCOPYf_angle_d0.68512169
ELECTRON MICROSCOPYf_dihedral_angle_d14.5185251
ELECTRON MICROSCOPYf_chiral_restr0.0461372
ELECTRON MICROSCOPYf_plane_restr0.0031511

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