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- EMDB-25076: LPHN3 (ADGRL3) 7TM domain bound to tethered agonist in complex wi... -

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Basic information

Entry
Database: EMDB / ID: EMD-25076
TitleLPHN3 (ADGRL3) 7TM domain bound to tethered agonist in complex with G protein heterotrimer
Map dataCryo-EM composite map for LPHN3 - miniG13 heterotrimer
Sample
  • Complex: Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in complex with mini-G13 protein
    • Protein or peptide: Isoform 1 of Adhesion G protein-coupled receptor L3
    • Protein or peptide: G protein subunit 13 (Gi2-mini-G13 chimera)
    • 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
  • Ligand: water
KeywordsAdhesion GPCR / LPHN3 / Latrophilin / ADGRL3 / tethered agonist / stalk / stachel / miniG13 / G13 heterotrimer / G protein / cryoEM / membrane protein
Function / homology
Function and homology information


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-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 ...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-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 / 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 / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
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 ...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
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 / Isoform 1 of Adhesion G protein-coupled receptor L3
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsBarros-Alvarez X / Panova O / Skiniotis G
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2022
Title: The tethered peptide activation mechanism of adhesion GPCRs.
Authors: Ximena Barros-Álvarez / Robert M Nwokonko / Alexander Vizurraga / Donna Matzov / Feng He / Makaía M Papasergi-Scott / Michael J Robertson / Ouliana Panova / Eliane Hadas Yardeni / Alpay B ...Authors: Ximena Barros-Álvarez / Robert M Nwokonko / Alexander Vizurraga / Donna Matzov / Feng He / Makaía M Papasergi-Scott / Michael J Robertson / Ouliana Panova / Eliane Hadas Yardeni / Alpay B Seven / Frank E Kwarcinski / Hongyu Su / Maria Claudia Peroto / Justin G Meyerowitz / Moran Shalev-Benami / Gregory G Tall / Georgios Skiniotis /
Abstract: Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions. ...Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions. Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers-N-terminal and C-terminal fragments-that remain non-covalently attached after receptors reach the cell surface. Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood. Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGRL3)). Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation.
History
DepositionOct 3, 2021-
Header (metadata) releaseApr 27, 2022-
Map releaseApr 27, 2022-
UpdateOct 9, 2024-
Current statusOct 9, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25076.png

Downloads & links

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Map

FileDownload / File: emd_25076.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM composite map for LPHN3 - miniG13 heterotrimer
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 360 pix.
= 306.756 Å		0.85 Å/pix.
x 360 pix.
= 306.756 Å		0.85 Å/pix.
x 360 pix.
= 306.756 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: 0.1
Minimum - Maximum-0.031035522 - 2.7190666
Average (Standard dev.)0.0006462257 (±0.018491086)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 306.756 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Local refinement of LPHN3 7TM domain

Fileemd_25076_additional_1.map
AnnotationLocal refinement of LPHN3 7TM domain
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Local refinement of miniG13 heterotrimer

Fileemd_25076_additional_2.map
AnnotationLocal refinement of miniG13 heterotrimer
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in co...

EntireName: Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in complex with mini-G13 protein
Components
  • Complex: Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in complex with mini-G13 protein
    • Protein or peptide: Isoform 1 of Adhesion G protein-coupled receptor L3
    • Protein or peptide: G protein subunit 13 (Gi2-mini-G13 chimera)
    • 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
  • Ligand: water

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Supramolecule #1: Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in co...

SupramoleculeName: Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in complex with mini-G13 protein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform 1 of Adhesion G protein-coupled receptor L3

MacromoleculeName: Isoform 1 of Adhesion G protein-coupled receptor L3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.313738 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: TNFAVLMAHV EVKHSDAVHD LLLDVITWVG ILLSLVCLLI CIFTFCFFRG LQSDRNTIHK NLCISLFVAE LLFLIGINRT DQPIACAVF AALLHFFFLA AFTWMFLEGV QLYIMLVEVF ESEHSRRKYF YLVGYGMPAL IVAVSAAVDY RSYGTDKVCW L RLDTYFIW ...String:
TNFAVLMAHV EVKHSDAVHD LLLDVITWVG ILLSLVCLLI CIFTFCFFRG LQSDRNTIHK NLCISLFVAE LLFLIGINRT DQPIACAVF AALLHFFFLA AFTWMFLEGV QLYIMLVEVF ESEHSRRKYF YLVGYGMPAL IVAVSAAVDY RSYGTDKVCW L RLDTYFIW SFIGPATLII MLNVIFLGIA LYKMFHHTAI LKPESGCLDN IKSWVIGAIA LLCLLGLTWA FGLMYINEST VI MAYLFTI FNSLQGMFIF IFHCVLQKKV RKEYGKCLRT HCCSGKSTES SIGSGKTSGS LEVLFQ

UniProtKB: Isoform 1 of Adhesion G protein-coupled receptor L3

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Macromolecule #2: G protein subunit 13 (Gi2-mini-G13 chimera)

MacromoleculeName: G protein subunit 13 (Gi2-mini-G13 chimera) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.5744 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTVSAEDK AAAERSKEID KCLSREKTYV KRLVKILLLG ADNSGKSTFL KQMRIIHGGS GGSGGTKGIH EYDFEIKNVP FKMVDVGGQ RSERKRWFEC FDSVTSILFL VDSSDFNRLT ESLNDFETIV NNRVFSNVSI ILFLNKTDLL EEKVQIVSIK D YFLEFEGD ...String:
MGSTVSAEDK AAAERSKEID KCLSREKTYV KRLVKILLLG ADNSGKSTFL KQMRIIHGGS GGSGGTKGIH EYDFEIKNVP FKMVDVGGQ RSERKRWFEC FDSVTSILFL VDSSDFNRLT ESLNDFETIV NNRVFSNVSI ILFLNKTDLL EEKVQIVSIK D YFLEFEGD PHCLRDVQKF LVECFRNKRR DQQQKPLYHH FTTAINTENA RLIFRDVKDT ILHDNLKQLM LQ

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.41693 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

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

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Macromolecule #4: 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: 4 / 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

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

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 3 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration4.5 mg/mL
BufferpH: 7.5
GridModel: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK II

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 57050 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2) / Number images used: 440914
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 3.2)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 3.2)
FSC plot (resolution estimation)

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