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- PDB-7ept: Structural basis for the tethered peptide activation of adhesion GPCRs -

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Entry
Database: PDB / ID: 7ept
TitleStructural basis for the tethered peptide activation of adhesion GPCRs
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Adhesion G-protein coupled receptor D1
  • Nanobody-35Single-domain antibody
KeywordsSTRUCTURAL PROTEIN / adhesion GPCR / GPR133
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
PALMITIC ACID / 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)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsPing, Y.-Q. / Xiao, P. / Yang, F. / Zhao, R.-J. / Guo, S.-C. / Yan, X. / Wu, X. / Liebscher, I. / Xu, H.E. / Sun, J.-P.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nature / Year: 2022
Title: Structural basis for the tethered peptide activation of adhesion GPCRs.
Authors: Yu-Qi Ping / Peng Xiao / Fan Yang / Ru-Jia Zhao / Sheng-Chao Guo / Xu Yan / Xiang Wu / Chao Zhang / Yan Lu / Fenghui Zhao / Fulai Zhou / Yue-Tong Xi / Wanchao Yin / Feng-Zhen Liu / Dong-Fang ...Authors: Yu-Qi Ping / Peng Xiao / Fan Yang / Ru-Jia Zhao / Sheng-Chao Guo / Xu Yan / Xiang Wu / Chao Zhang / Yan Lu / Fenghui Zhao / Fulai Zhou / Yue-Tong Xi / Wanchao Yin / Feng-Zhen Liu / Dong-Fang He / Dao-Lai Zhang / Zhong-Liang Zhu / Yi Jiang / Lutao Du / Shi-Qing Feng / Torsten Schöneberg / Ines Liebscher / H Eric Xu / Jin-Peng Sun /
Abstract: Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes. Many aGPCRs are activated by a conserved internal (tethered) agonist ...Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes. Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with G: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-β-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W and the constitution of a hydrogen-bond network formed by Q/Y and the P/VφφG motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and G coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common G-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with G. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their G coupling.
History
DepositionApr 27, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 11, 2022Provider: repository / Type: Initial release

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Structure visualization

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MolmilJmol/JSmol

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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: Nanobody-35
R: Adhesion G-protein coupled receptor D1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)138,3166
Polymers138,0605
Non-polymers2561
Water0
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


Mass: 45727.441 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR133, ADGRD1,PGR25 / Production host: Spodoptera frugiperda (fall armyworm)
#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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody / Protein / Non-polymers , 3 types, 3 molecules NR

#4: Antibody Nanobody-35 / Single-domain antibody


Mass: 13885.439 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein Adhesion G-protein coupled receptor D1 / G-protein coupled receptor 133 / G-protein coupled receptor PGR25


Mass: 31096.748 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADGRD1, GPR133, PGR25 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q6QNK2
#6: Chemical ChemComp-PLM / PALMITIC ACID / Palmitic acid


Mass: 256.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H32O2

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Details

Has ligand of interestN

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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
1GPR133-Ga-Nb35 complexCOMPLEX#1-#50MULTIPLE SOURCES
2GPR133-GaCOMPLEX#1-#3, #51RECOMBINANT
3Nb35COMPLEX#41RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32synthetic construct (others)32630
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
32Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.4
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: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 575193 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048007
ELECTRON MICROSCOPYf_angle_d0.49110857
ELECTRON MICROSCOPYf_dihedral_angle_d4.1661101
ELECTRON MICROSCOPYf_chiral_restr0.041239
ELECTRON MICROSCOPYf_plane_restr0.0031381

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