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- PDB-8xzg: Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex -

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Basic information

Entry
Database: PDB / ID: 8xzg
TitleCryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex
Components
  • Apelin receptor
  • Apelin-13
  • 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
  • Guanine nucleotide-binding protein G(i) subunit alpha-1
KeywordsMEMBRANE PROTEIN / APLNR / apelin / Class A GPCR / Structural protein
Function / homology
Function and homology information


apelin receptor binding / positive regulation of corticotropin-releasing hormone secretion / positive regulation of corticotropin secretion / : / 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 ...apelin receptor binding / positive regulation of corticotropin-releasing hormone secretion / positive regulation of corticotropin secretion / : / 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 / positive regulation of heat generation / 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 / endocardial cushion formation / positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / regulation of the force of heart contraction / coronary vasculature development / adult heart development / vasculature development / negative regulation of systemic arterial blood pressure / 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 vasoconstriction / ventricular septum morphogenesis / blood vessel development / heart looping / negative regulation of vascular associated smooth muscle cell proliferation / positive regulation of phosphorylation / vasculogenesis / positive regulation of heart rate / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / negative regulation of blood pressure / T cell migration / Adenylate cyclase inhibitory pathway / gastrulation / D2 dopamine receptor binding / response to prostaglandin E / lactation / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / regulation of mitotic spindle organization / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / response to peptide hormone / hormone activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / positive regulation of miRNA transcription / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / 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 / positive regulation of angiogenesis / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / 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
Similarity search - Function
Apelin / APJ endogenous ligand / Apelin receptor / : / 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 ...Apelin / APJ endogenous ligand / Apelin receptor / : / 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 / G protein beta WD-40 repeat protein / 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. / 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
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 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Apelin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWang, W. / Ji, S. / Zhang, Y.
Funding support China, 2items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China) China
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell / Year: 2024
Title: Structure-based design of non-hypertrophic apelin receptor modulator.
Authors: Wei-Wei Wang / Su-Yu Ji / Wenjia Zhang / Junxia Zhang / Chenxi Cai / Rubi Hu / Shao-Kun Zang / Luwei Miao / Haomang Xu / Li-Nan Chen / Zongkuai Yang / Jia Guo / Jiao Qin / Dan-Dan Shen / ...Authors: Wei-Wei Wang / Su-Yu Ji / Wenjia Zhang / Junxia Zhang / Chenxi Cai / Rubi Hu / Shao-Kun Zang / Luwei Miao / Haomang Xu / Li-Nan Chen / Zongkuai Yang / Jia Guo / Jiao Qin / Dan-Dan Shen / Ping Liang / Yan Zhang / Yan Zhang /
Abstract: Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse ...Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the β-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-G complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.
History
DepositionJan 21, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
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Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Jul 16, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 16, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
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
L: Apelin-13
R: Apelin receptor


Theoretical massNumber of molelcules
Total (without water)129,7955
Polymers129,7955
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Cell (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1


Mass: 37285.734 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Cell (production host): Sf9 / 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 / Cell (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768
#4: Protein/peptide Apelin-13


Mass: 1537.830 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APLN, APEL / Production host: Homo sapiens (human) / References: UniProt: Q9ULZ1
#5: Protein Apelin receptor / Angiotensin receptor-like 1 / G-protein coupled receptor APJ / G-protein coupled receptor HG11


Mass: 42696.301 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APLNR, AGTRL1, APJ / Cell (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P35414
Has ligand of interestN
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: Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingElectron dose: 62.4 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2703505
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 201936 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0087320
ELECTRON MICROSCOPYf_angle_d0.8649914
ELECTRON MICROSCOPYf_dihedral_angle_d14.1274346
ELECTRON MICROSCOPYf_chiral_restr0.2721135
ELECTRON MICROSCOPYf_plane_restr0.0051248

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