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- PDB-7xkd: Cryo-EM structure of DHEA-ADGRG2-BT-Gs complex -

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Basic information

Entry
Database: PDB / ID: 7xkd
TitleCryo-EM structure of DHEA-ADGRG2-BT-Gs complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Adhesion G-protein coupled receptor G2
  • NB35
KeywordsMEMBRANE PROTEIN
Function / homology
Function and homology information


PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / intracellular transport / positive regulation of cAMP-mediated signaling / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity ...PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / intracellular transport / positive regulation of cAMP-mediated signaling / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / trans-Golgi network membrane / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / bone development / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / cognition / photoreceptor disc membrane / platelet aggregation / Adrenaline,noradrenaline inhibits insulin secretion / positive regulation of GTPase activity / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / 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 / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / apical plasma membrane / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like ...GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / 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 S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain 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 / 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
3-BETA-HYDROXY-5-ANDROSTEN-17-ONE / 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 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adhesion G-protein coupled receptor G2
Similarity search - Component
Biological speciesHomo sapiens (human)
Camelus bactrianus (Bactrian camel)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.4 Å
AuthorsGuo, S.C. / Xiao, P. / Lin, H. / Sun, J.P. / Yu, X.
Funding support China, 4items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)92057121 China
National Natural Science Foundation of China (NSFC)32130055 China
National Science Foundation (NSF, China)81825022 China
National Natural Science Foundation of China (NSFC)ZR2021ZD18 China
CitationJournal: Nat Chem Biol / Year: 2022
Title: Structures of the ADGRG2-G complex in apo and ligand-bound forms.
Authors: Hui Lin / Peng Xiao / Rui-Qian Bu / Shengchao Guo / Zhao Yang / Daopeng Yuan / Zhong-Liang Zhu / Chuan-Xin Zhang / Qing-Tao He / Chao Zhang / Yu-Qi Ping / Ru-Jia Zhao / Chuan-Shun Ma / Chang- ...Authors: Hui Lin / Peng Xiao / Rui-Qian Bu / Shengchao Guo / Zhao Yang / Daopeng Yuan / Zhong-Liang Zhu / Chuan-Xin Zhang / Qing-Tao He / Chao Zhang / Yu-Qi Ping / Ru-Jia Zhao / Chuan-Shun Ma / Chang-Hao Liu / Xiao-Ning Zhang / Dan Jiang / Shaohui Huang / Yue-Tong Xi / Dao-Lai Zhang / Chen-Yang Xue / Bai-Sheng Yang / Jian-Yuan Li / Hao-Cheng Lin / Xu-Hui Zeng / Han Zhao / Wen-Ming Xu / Fan Yi / Zhongmin Liu / Jin-Peng Sun / Xiao Yu /
Abstract: Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an ...Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a G trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-G provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.
History
DepositionApr 19, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 10, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 15, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
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
N: NB35
R: Adhesion G-protein coupled receptor G2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,3846
Polymers140,0965
Non-polymers2881
Water181
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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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 45683.434 Da / Num. of mol.: 1
Mutation: S54N, G226A, E268A, N271K, K274D, R280K, T284D, I285T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P63092
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39489.160 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 6375.332 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P59768

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Antibody / Protein , 2 types, 2 molecules NR

#4: Antibody NB35


Mass: 13885.439 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Camelus bactrianus (Bactrian camel) / Production host: Escherichia coli (E. coli)
#5: Protein Adhesion G-protein coupled receptor G2 / G-protein coupled receptor 64 / Mouse epididymis-specific protein 6 / Me6


Mass: 34662.309 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: The C-terminal (892-916) is due to the replacement of GPR120 tail.
Source: (gene. exp.) Homo sapiens (human) / Gene: Adgrg2, Gpr64, Me6 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q8CJ12

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Non-polymers , 2 types, 2 molecules

#6: Chemical ChemComp-AND / 3-BETA-HYDROXY-5-ANDROSTEN-17-ONE / Dehydroepiandrosterone


Mass: 288.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H28O2 / Comment: hormone*YM
#7: Water ChemComp-HOH / water / 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
1Adhesion G-protein coupled receptor G2COMPLEX#1-#50RECOMBINANT
2Adhesion G-proteinCOMPLEX#1-#31RECOMBINANT
3NB35COMPLEX#41RECOMBINANT
4Adhesion G-protein coupled receptor G2COMPLEX#51RECOMBINANT
Molecular weightValue: 0.13 MDa / Experimental value: YES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Camelus bactrianus (Bactrian camel)9837
43Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Baculovirus expression vector pFastBac1-HM274590
32Escherichia coli (E. coli)562
43Baculovirus expression vector pFastBac1-HM274590
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1039271 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048134
ELECTRON MICROSCOPYf_angle_d0.61411021
ELECTRON MICROSCOPYf_dihedral_angle_d4.1791103
ELECTRON MICROSCOPYf_chiral_restr0.0421244
ELECTRON MICROSCOPYf_plane_restr0.0051395

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