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- PDB-8xqe: Cryo-EM structure of human dimeric APJR-Gi complex with apelin-13. -

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Basic information

Entry
Database: PDB / ID: 8xqe
TitleCryo-EM structure of human dimeric APJR-Gi complex with apelin-13.
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • Apelin-13
  • G protein subunit alpha i1
  • Soluble cytochrome b562,Apelin receptor
  • scFv16
KeywordsSIGNALING PROTEIN / GPCR / APJR / Gi / Apelin-13 / Dimeric
Function / homology
Function and homology information


apelin receptor binding / apelin receptor activity / apelin receptor signaling pathway / mechanoreceptor activity / regulation of gap junction assembly / positive regulation of G protein-coupled receptor internalization / vascular associated smooth muscle cell differentiation / atrioventricular valve development / regulation of body fluid levels / venous blood vessel development ...apelin receptor binding / apelin receptor activity / apelin receptor signaling pathway / mechanoreceptor activity / regulation of gap junction assembly / positive regulation of G protein-coupled receptor internalization / vascular associated smooth muscle cell differentiation / atrioventricular valve development / regulation of body fluid levels / venous blood vessel development / negative regulation of fibroblast growth factor receptor signaling pathway / positive regulation of heart contraction / positive regulation of cardiac muscle hypertrophy in response to stress / drinking behavior / positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / endocardial cushion formation / coronary vasculature development / vasculature development / adult heart development / G protein-coupled peptide receptor activity / positive regulation of vascular endothelial cell proliferation / aorta development / negative regulation of cardiac muscle hypertrophy in response to stress / negative regulation of cAMP-mediated signaling / ventricular septum morphogenesis / blood vessel development / heart looping / negative regulation of vascular associated smooth muscle cell proliferation / vasculogenesis / G protein-coupled serotonin receptor binding / negative regulation of blood pressure / gastrulation / lactation / positive regulation of release of sequestered calcium ion into cytosol / Peptide ligand-binding receptors / electron transport chain / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / hormone activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / positive regulation of miRNA transcription / G-protein beta/gamma-subunit complex binding / 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 / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / positive regulation of angiogenesis / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / 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 / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / signaling receptor activity / Thrombin signalling through proteinase activated receptors (PARs) / heart development / regulation of gene expression / GTPase binding / Ca2+ pathway / retina development in camera-type eye / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / angiogenesis / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Ras protein signal transduction / periplasmic space / Extra-nuclear estrogen signaling / electron transfer activity / cell population proliferation
Similarity search - Function
Apelin / APJ endogenous ligand / Apelin receptor / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion ...Apelin / APJ endogenous ligand / Apelin receptor / : / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(i) subunit alpha-1 / Soluble cytochrome b562 / Apelin receptor / 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 / Apelin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.48 Å
AuthorsYue, Y. / Liu, L.E. / Wu, L.J. / Xu, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Structural insights into the regulation of monomeric and dimeric apelin receptor.
Authors: Yang Yue / Lier Liu / Lijie Wu / Chanjuan Xu / Man Na / Shenhui Liu / Yuxuan Liu / Fei Li / Junlin Liu / Songting Shi / Hui Lei / Minxuan Zhao / Tianjie Yang / Wei Ji / Arthur Wang / Michael ...Authors: Yang Yue / Lier Liu / Lijie Wu / Chanjuan Xu / Man Na / Shenhui Liu / Yuxuan Liu / Fei Li / Junlin Liu / Songting Shi / Hui Lei / Minxuan Zhao / Tianjie Yang / Wei Ji / Arthur Wang / Michael A Hanson / Raymond C Stevens / Jianfeng Liu / Fei Xu /
Abstract: The apelin receptor (APJR) emerges as a promising drug target for cardiovascular health and muscle regeneration. While prior research unveiled the structural versatility of APJR in coupling to Gi ...The apelin receptor (APJR) emerges as a promising drug target for cardiovascular health and muscle regeneration. While prior research unveiled the structural versatility of APJR in coupling to Gi proteins as a monomer or dimer, the dynamic regulation within the APJR dimer during activation remains poorly understood. In this study, we present the structures of the APJR dimer and monomer complexed with its endogenous ligand apelin-13. In the dimeric structure, apelin-13 binds exclusively to one protomer that is coupled with Gi proteins, revealing a distinct ligand-binding behavior within APJR homodimers. Furthermore, binding of an antagonistic antibody induces a more compact dimerization by engaging both protomers. Notably, structural analyses of the APJR dimer complexed with an agonistic antibody, with or without Gi proteins, suggest that G protein coupling may promote the dissociation of the APJR dimer during activation. These findings underscore the intricate interplay between ligands, dimerization, and G protein coupling in regulating APJR signaling pathways.
History
DepositionJan 5, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: G protein subunit alpha i1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Soluble cytochrome b562,Apelin receptor
S: scFv16
D: Apelin-13
Q: Soluble cytochrome b562,Apelin receptor


Theoretical massNumber of molelcules
Total (without water)223,8597
Polymers223,8597
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 3 molecules ARQ

#1: Protein G protein subunit alpha i1


Mass: 40616.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: A0A096MZM0
#4: Protein Soluble cytochrome b562,Apelin receptor / Cytochrome b-562 / Angiotensin receptor-like 1 / G-protein coupled receptor APJ / G-protein coupled ...Cytochrome b-562 / Angiotensin receptor-like 1 / G-protein coupled receptor APJ / G-protein coupled receptor HG11


Mass: 54312.578 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: cybC, APLNR, AGTRL1, APJ / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P0ABE7, UniProt: P35414

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BC

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


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / 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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Antibody / Protein/peptide , 2 types, 2 molecules SD

#5: Antibody scFv16


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#6: Protein/peptide Apelin-13


Mass: 1554.860 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APLN, APEL / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9ULZ1

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Details

Has protein modificationY

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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

ComponentName: dimeric APJR-Gi complex with apelin-13 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.48 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 24309 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00411620
ELECTRON MICROSCOPYf_angle_d0.76915771
ELECTRON MICROSCOPYf_dihedral_angle_d4.5661570
ELECTRON MICROSCOPYf_chiral_restr0.0441799
ELECTRON MICROSCOPYf_plane_restr0.0071969

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