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- EMDB-32817: Cryo-EM structure of the adhesion GPCR ADGRD1 in complex with miniGs -

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Basic information

Entry
Database: EMDB / ID: EMD-32817
TitleCryo-EM structure of the adhesion GPCR ADGRD1 in complex with miniGs
Map data
Sample
  • Complex: The adhesion GPCR ADGRD1 in complex with miniGs
    • Complex: The adhesion GPCR ADGRD1 in complex with miniGs
      • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
      • Protein or peptide: Adhesion G-protein coupled receptor D1
    • Complex: Nanobody Nb35
      • Protein or peptide: Nanobody Nb35
Function / homology
Function and homology information


plasma membrane => GO:0005886 / G protein-coupled receptor activity / Olfactory Signaling Pathway / Activation of the phototransduction cascade / 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 ...plasma membrane => GO:0005886 / G protein-coupled receptor activity / Olfactory Signaling Pathway / Activation of the phototransduction cascade / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / membrane => GO:0016020 / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Pentraxin-related / Pentraxin (PTX) domain profile. / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GPS 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 ...Pentraxin-related / Pentraxin (PTX) domain profile. / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GPS 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, 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 / Concanavalin A-like lectin/glucanase domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
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 D1
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsQu X / Qiu N / Wang M / Zhao Q / Wu B
Funding support China, 5 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)31971362 China
Ministry of Science and Technology (MoST, China)2018YFA0507000 China
Chinese Academy of SciencesXDB37030100 China
Chinese Academy of SciencesJCYJ-SHFY-2021-008 China
CitationJournal: Nature / Year: 2022
Title: Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1.
Authors: Xiangli Qu / Na Qiu / Mu Wang / Bingjie Zhang / Juan Du / Zhiwei Zhong / Wei Xu / Xiaojing Chu / Limin Ma / Cuiying Yi / Shuo Han / Wenqing Shui / Qiang Zhao / Beili Wu /
Abstract: Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis. ...Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis. An intrinsic manner of activation that involves a tethered agonist in the N-terminal region of the receptor has been proposed for the aGPCRs, but its molecular mechanism remains elusive. Here we report the G protein-bound structures of ADGRD1 and ADGRF1, which exhibit many unique features with regard to the tethered agonism. The stalk region that proceeds the first transmembrane helix acts as the tethered agonist by forming extensive interactions with the transmembrane domain; these interactions are mostly conserved in ADGRD1 and ADGRF1, suggesting that a common stalk-transmembrane domain interaction pattern is shared by members of the aGPCR family. A similar stalk binding mode is observed in the structure of autoproteolysis-deficient ADGRF1, supporting a cleavage-independent manner of receptor activation. The stalk-induced activation is facilitated by a cascade of inter-helix interaction cores that are conserved in positions but show sequence variability in these two aGPCRs. Furthermore, the intracellular region of ADGRF1 contains a specific lipid-binding site, which proves to be functionally important and may serve as the recognition site for the previously discovered endogenous ADGRF1 ligand synaptamide. These findings highlight the diversity and complexity of the signal transduction mechanisms of the aGPCRs.
History
DepositionFeb 5, 2022-
Header (metadata) releaseApr 27, 2022-
Map releaseApr 27, 2022-
UpdateMay 11, 2022-
Current statusMay 11, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_32817.png

Downloads & links

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Map

FileDownload / File: emd_32817.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.071 Å
Density
Contour LevelBy AUTHOR: 0.0115
Minimum - Maximum-0.066392764 - 0.11840149
Average (Standard dev.)9.198281e-05 (±0.0019522042)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 274.176 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : The adhesion GPCR ADGRD1 in complex with miniGs

EntireName: The adhesion GPCR ADGRD1 in complex with miniGs
Components
  • Complex: The adhesion GPCR ADGRD1 in complex with miniGs
    • Complex: The adhesion GPCR ADGRD1 in complex with miniGs
      • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
      • Protein or peptide: Adhesion G-protein coupled receptor D1
    • Complex: Nanobody Nb35
      • Protein or peptide: Nanobody Nb35

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Supramolecule #1: The adhesion GPCR ADGRD1 in complex with miniGs

SupramoleculeName: The adhesion GPCR ADGRD1 in complex with miniGs / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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Supramolecule #2: The adhesion GPCR ADGRD1 in complex with miniGs

SupramoleculeName: The adhesion GPCR ADGRD1 in complex with miniGs / type: complex / Chimera: Yes / ID: 2 / Parent: 1 / Macromolecule list: #1-#3, #5
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)

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Supramolecule #3: Nanobody Nb35

SupramoleculeName: Nanobody Nb35 / type: complex / Chimera: Yes / ID: 3 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Lama glama (llama)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.387094 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGHHHHHHEN LYFQGIEKQL QKDKQVYRAT HRLLLLGADN SGKSTIVKQM RILHGGSGGS GGTSGIFETK FQVDKVNFHM FDVGGQRDE RRKWIQCFND VTAIIFVVDS SDYNRLQEAL NDFKSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED Y FPEFARYT ...String:
MGHHHHHHEN LYFQGIEKQL QKDKQVYRAT HRLLLLGADN SGKSTIVKQM RILHGGSGGS GGTSGIFETK FQVDKVNFHM FDVGGQRDE RRKWIQCFND VTAIIFVVDS SDYNRLQEAL NDFKSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED Y FPEFARYT TPEDATPEPG EDPRVTRAKY FIRDEFLRIS TASGDGRHYC YPHFTCAVDT ENARRIFNDC RDIIQRMHLR QY ELL

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.744371 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI ...String:
MHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT REGNVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWN

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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Macromolecule #4: Nanobody Nb35

MacromoleculeName: Nanobody Nb35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 17.540746 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MGMKYLLPTA AAGLLLLAAQ PAMAQVQLQE SGGGLVQPGG SLRLSCAASG FTFSNYKMNW VRQAPGKGLE WVSDISQSGA SISYTGSVK GRFTISRDNA KNTLYLQMNS LKPEDTAVYY CARCPAPFTR DCFDVTSTTY AYRGQGTQVT VSSHHHHHHE P EA

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Macromolecule #5: Adhesion G-protein coupled receptor D1

MacromoleculeName: Adhesion G-protein coupled receptor D1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.168559 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFAGAPT NFAILMQVVP LELARGHQVA LSSISYVGCS LSVLCLVATL VTFAVLSSVS TIRNQRYHIH ANLSFAVLV AQVLLLISFR LEPGTTPCQV MAVLLHYFFL SAFAWMLVEG LHLYSMVIKV FGSEDSKHRY YYGMGWGFPL L ICIISLSF ...String:
MKTIIALSYI FCLVFAGAPT NFAILMQVVP LELARGHQVA LSSISYVGCS LSVLCLVATL VTFAVLSSVS TIRNQRYHIH ANLSFAVLV AQVLLLISFR LEPGTTPCQV MAVLLHYFFL SAFAWMLVEG LHLYSMVIKV FGSEDSKHRY YYGMGWGFPL L ICIISLSF AMDSYGTSNN CWLSLASGAI WAFVAPALFV IVVNIGILIA VTRVISQISA DNYKIHGDPS AFKLTAKAVA VL LPILGTS WVFGVLAVNG CAVVFQYMFA TLNSLQGLFI FLFHCLLNSE VRAAFKHKTK VWSLTEFLEV LFQGPWSHPQ FEK GGGSGG GSGGSAWSHP QFEKDYKDDD DK

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 70.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: OTHER
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1266674

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