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- EMDB-43523: Latrophilin-3 (ADGRL3) HormR and GAIN domains in the context of t... -

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Basic information

Entry
Database: EMDB / ID: EMD-43523
TitleLatrophilin-3 (ADGRL3) HormR and GAIN domains in the context of the holoreceptor
Map data
Sample
  • Complex: Latrophilin3/ADGRL3 HormR+GAIN/7TM holoreceptor in complex with synthetic antibody fragment
    • Complex: Latrophilin3/ADGRL3
      • Protein or peptide: Isoform 4 of Adhesion G protein-coupled receptor L3
      • Protein or peptide: Isoform 4 of Adhesion G protein-coupled receptor L3
    • Complex: Synthetic antibody fragment
      • Protein or peptide: sAB Light Chain
      • Protein or peptide: sAB Heavy Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Keywordsadhesion GPCR / GAIN domain / cell-cell adhesion / synapse / SIGNALING PROTEIN
Function / homology
Function and homology information


Rho-activating G protein-coupled receptor signaling pathway / cell adhesion mediator activity / excitatory synapse assembly / : / synapse assembly / molecular condensate scaffold activity / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / neuron migration / cell-cell junction ...Rho-activating G protein-coupled receptor signaling pathway / cell adhesion mediator activity / excitatory synapse assembly / : / synapse assembly / molecular condensate scaffold activity / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / neuron migration / cell-cell junction / carbohydrate binding / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / axon / calcium ion binding / glutamatergic synapse / membrane / plasma membrane
Similarity search - Function
GPCR, family 2, latrophilin, C-terminal / GPCR, family 2, latrophilin / Latrophilin Cytoplasmic C-terminal region / D-galactoside/L-rhamnose binding SUEL lectin domain superfamily / D-galactoside/L-rhamnose binding SUEL lectin domain / D-galactoside/L-rhamnose binding SUEL lectin domain / SUEL-type lectin domain profile. / GAIN domain, N-terminal / AGRL2-4 GAIN subdomain A / Olfactomedin-like domain ...GPCR, family 2, latrophilin, C-terminal / GPCR, family 2, latrophilin / Latrophilin Cytoplasmic C-terminal region / D-galactoside/L-rhamnose binding SUEL lectin domain superfamily / D-galactoside/L-rhamnose binding SUEL lectin domain / D-galactoside/L-rhamnose binding SUEL lectin domain / SUEL-type lectin domain profile. / GAIN domain, N-terminal / AGRL2-4 GAIN subdomain A / Olfactomedin-like domain / Olfactomedin-like domain / Olfactomedin-like domain profile. / Olfactomedin-like domains / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / : / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / 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.
Similarity search - Domain/homology
Adhesion G protein-coupled receptor L3
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsKordon SP / Bandekar SJ / Arac D
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM148412 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM134035-01 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)F32 GM142266 United States
CitationJournal: Nat Commun / Year: 2024
Title: Conformational coupling between extracellular and transmembrane domains modulates holo-adhesion GPCR function.
Authors: Szymon P Kordon / Kristina Cechova / Sumit J Bandekar / Katherine Leon / Przemysław Dutka / Gracie Siffer / Anthony A Kossiakoff / Reza Vafabakhsh / Demet Araç /
Abstract: Adhesion G Protein-Coupled Receptors (aGPCRs) are key cell-adhesion molecules involved in numerous physiological functions. aGPCRs have large multi-domain extracellular regions (ECRs) containing a ...Adhesion G Protein-Coupled Receptors (aGPCRs) are key cell-adhesion molecules involved in numerous physiological functions. aGPCRs have large multi-domain extracellular regions (ECRs) containing a conserved GAIN domain that precedes their seven-pass transmembrane domain (7TM). Ligand binding and mechanical force applied on the ECR regulate receptor function. However, how the ECR communicates with the 7TM remains elusive, because the relative orientation and dynamics of the ECR and 7TM within a holoreceptor is unclear. Here, we describe the cryo-EM reconstruction of an aGPCR, Latrophilin3/ADGRL3, and reveal that the GAIN domain adopts a parallel orientation to the transmembrane region and has constrained movement. Single-molecule FRET experiments unveil three slow-exchanging FRET states of the ECR relative to the transmembrane region within the holoreceptor. GAIN-targeted antibodies, and cancer-associated mutations at the GAIN-7TM interface, alter FRET states, cryo-EM conformations, and receptor signaling. Altogether, this data demonstrates conformational and functional coupling between the ECR and 7TM, suggesting an ECR-mediated mechanism for aGPCR activation.
History
DepositionJan 26, 2024-
Header (metadata) releaseDec 11, 2024-
Map releaseDec 11, 2024-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43523.png

Downloads & links

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Map

FileDownload / File: emd_43523.map.gz / Format: CCP4 / Size: 669.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.67 Å/pix.
x 560 pix.
= 376.04 Å		0.67 Å/pix.
x 560 pix.
= 376.04 Å		0.67 Å/pix.
x 560 pix.
= 376.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6715 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.135
Minimum - Maximum-0.6933366 - 1.1857325
Average (Standard dev.)0.0001379278 (±0.00708544)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions560560560
Spacing560560560
CellA=B=C: 376.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_43523_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_43523_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Latrophilin3/ADGRL3 HormR+GAIN/7TM holoreceptor in complex with s...

EntireName: Latrophilin3/ADGRL3 HormR+GAIN/7TM holoreceptor in complex with synthetic antibody fragment
Components
  • Complex: Latrophilin3/ADGRL3 HormR+GAIN/7TM holoreceptor in complex with synthetic antibody fragment
    • Complex: Latrophilin3/ADGRL3
      • Protein or peptide: Isoform 4 of Adhesion G protein-coupled receptor L3
      • Protein or peptide: Isoform 4 of Adhesion G protein-coupled receptor L3
    • Complex: Synthetic antibody fragment
      • Protein or peptide: sAB Light Chain
      • Protein or peptide: sAB Heavy Chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Latrophilin3/ADGRL3 HormR+GAIN/7TM holoreceptor in complex with s...

SupramoleculeName: Latrophilin3/ADGRL3 HormR+GAIN/7TM holoreceptor in complex with synthetic antibody fragment
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50 KDa

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Supramolecule #2: Latrophilin3/ADGRL3

SupramoleculeName: Latrophilin3/ADGRL3 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Synthetic antibody fragment

SupramoleculeName: Synthetic antibody fragment / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: synthetic construct (others)

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Macromolecule #1: Isoform 4 of Adhesion G protein-coupled receptor L3

MacromoleculeName: Isoform 4 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: 41.641762 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDAMA QIPALEESCE AVEAREIMWF KTRQGQIAKQ PCPAGTIGVS TYLCLAPDGI WDPQGPDLSN CSSPWVNHIT QKLKSGETA ANIARELAEQ TRNHLNAGDI TYSVRAMDQL VGLLDVQLRN LTPGGKDSAA RSLNKLQKRE RSCRAYVQAM V ETVNNLLQ ...String:
DYKDDDDAMA QIPALEESCE AVEAREIMWF KTRQGQIAKQ PCPAGTIGVS TYLCLAPDGI WDPQGPDLSN CSSPWVNHIT QKLKSGETA ANIARELAEQ TRNHLNAGDI TYSVRAMDQL VGLLDVQLRN LTPGGKDSAA RSLNKLQKRE RSCRAYVQAM V ETVNNLLQ PQALNAWRDL TTSDQLRAAT MLLHTVEESA FVLADNLLKT DIVRENTDNI KLEVARLSTE GNLEDLKFPE NM GHGSTIQ LSANTLKQNG RNGEIRVAFV LYNNLGPYLS TENASMKLGT EALSTNHSVI VNSPVITAAI NKEFSNKVYL ADP VVFTVK HIKQSEENFN PNCSFWSYSK RTMTGYWSTQ GCRLLTTNKT HTTCSCNHL

UniProtKB: Adhesion G protein-coupled receptor L3

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Macromolecule #2: Isoform 4 of Adhesion G protein-coupled receptor L3

MacromoleculeName: Isoform 4 of Adhesion G protein-coupled receptor L3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 35.83925 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 INYEDNRPFI KSWVIGAIAL LCLLGLTWAF GL MYINEST VIMAYLFTIF NSLQGMFIFI FHCVLQKKVR KEYGKCLRTH CCSGKSTESS IGSGKTSGSH HHHHHHH

UniProtKB: Adhesion G protein-coupled receptor L3

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Macromolecule #3: sAB Light Chain

MacromoleculeName: sAB Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 23.329863 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQSGQYPLTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQSGQYPLTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #4: sAB Heavy Chain

MacromoleculeName: sAB Heavy Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 25.221016 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NISSSYIHWV RQAPGKGLEW VASISPYSGY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARHNYWQWWE YSYALDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NISSSYIHWV RQAPGKGLEW VASISPYSGY TSYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARHNYWQWWE YSYALDYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY F PEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKKVEPK SCDKTHT

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration2.5 mg/mL
BufferpH: 7.5
Component:
ConcentrationName
30.0 mMHEPES
150.0 mMNaCl
0.00075 %LMNG
0.00025 %GDN
0.0001 %CHS
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 20 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283.15 K / Instrument: FEI VITROBOT MARK IV
DetailsMonodisperse protein sample in detergent buffer

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 1.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2621532
CTF correctionSoftware - Name: cryoSPARC (ver. 4.4) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 96958
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.4)
FSC plot (resolution estimation)

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