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- EMDB-25076: LPHN3 (ADGRL3) 7TM domain bound to tethered agonist in complex wi... -
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Open data
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Basic information
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Title | LPHN3 (ADGRL3) 7TM domain bound to tethered agonist in complex with G protein heterotrimer | |||||||||
![]() | Cryo-EM composite map for LPHN3 - miniG13 heterotrimer | |||||||||
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Function / homology | ![]() cell-cell adhesion via plasma-membrane adhesion molecules / plasma membrane => GO:0005886 / synapse assembly / G protein-coupled receptor activity / neuron migration / 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 ...cell-cell adhesion via plasma-membrane adhesion molecules / plasma membrane => GO:0005886 / synapse assembly / G protein-coupled receptor activity / neuron migration / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / brain development / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / 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 / 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 / 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 / cell-cell junction / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / carbohydrate binding / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / membrane => GO:0016020 / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / axon / GTPase activity / glutamatergic synapse / synapse / calcium ion binding / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
![]() | Barros-Alvarez X / Panova O / Skiniotis G | |||||||||
Funding support | 1 items
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 1.5 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 20 KB 20 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() ![]() | 13.1 KB 13 KB | Display Display | ![]() |
Images | ![]() | 48.4 KB | ||
Others | ![]() ![]() | 844.3 KB 1.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 332.6 KB | Display | ![]() |
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Full document | ![]() | 332.2 KB | Display | |
Data in XML | ![]() | 12.9 KB | Display | |
Data in CIF | ![]() | 17.5 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7sf7MC ![]() 7sf8C C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
File | ![]() | ||||||||||||||||||||
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Annotation | Cryo-EM composite map for LPHN3 - miniG13 heterotrimer | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.8521 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: Local refinement of LPHN3 7TM domain
File | emd_25076_additional_1.map | ||||||||||||
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Annotation | Local refinement of LPHN3 7TM domain | ||||||||||||
Projections & Slices |
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Density Histograms |
-Additional map: Local refinement of miniG13 heterotrimer
File | emd_25076_additional_2.map | ||||||||||||
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Annotation | Local refinement of miniG13 heterotrimer | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in co...
Entire | Name: Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in complex with mini-G13 protein |
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Components |
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-Supramolecule #1: Latrophilin 3 (ADGRL3) 7TM domain bound to tethered agonist in co...
Supramolecule | Name: 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 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Macromolecule #1: Isoform 1 of Adhesion G protein-coupled receptor L3
Macromolecule | Name: Isoform 1 of Adhesion G protein-coupled receptor L3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 34.313738 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #2: G protein subunit 13 (Gi2-mini-G13 chimera)
Macromolecule | Name: G protein subunit 13 (Gi2-mini-G13 chimera) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 26.5744 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: 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 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 37.41693 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: 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 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #5: water
Macromolecule | Name: water / type: ligand / ID: 5 / Number of copies: 3 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 4.5 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: UltrAuFoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK II |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 1.1 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 70.0 µm / Calibrated magnification: 57050 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |