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- PDB-8xzg: Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex -
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Open data
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Basic information
Entry | Database: PDB / ID: 8xzg | |||||||||||||||||||||||||||||||||||||||||||||
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Title | Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex | |||||||||||||||||||||||||||||||||||||||||||||
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![]() | MEMBRANE PROTEIN / APLNR / apelin / Class A GPCR / Structural protein | |||||||||||||||||||||||||||||||||||||||||||||
Function / homology | ![]() 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 cAMP-mediated signaling / 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 / adult heart development / coronary vasculature development / vasculature development / G protein-coupled peptide receptor activity / positive regulation of vascular endothelial cell proliferation / negative regulation of cardiac muscle hypertrophy in response to stress / aorta development / ventricular septum morphogenesis / blood vessel development / heart looping / negative regulation of vascular associated smooth muscle cell proliferation / adenylate cyclase inhibitor activity / vasculogenesis / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / response to prostaglandin E / lactation / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / gastrulation / negative regulation of blood pressure / 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 / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / hormone activity / response to peptide hormone / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / positive regulation of miRNA transcription / G-protein beta/gamma-subunit complex binding / centriolar satellite / 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 / positive regulation of angiogenesis / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / 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 / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / 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 activity / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / G protein activity Similarity search - Function | |||||||||||||||||||||||||||||||||||||||||||||
Biological species | ![]() | |||||||||||||||||||||||||||||||||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||||||||||||||||||||||||||||||||||||||
![]() | Wang, W. / Ji, S. / Zhang, Y. | |||||||||||||||||||||||||||||||||||||||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 177.1 KB | Display | ![]() |
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PDB format | ![]() | 133.9 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 392.4 KB | Display | ![]() |
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Full document | ![]() | 403.6 KB | Display | |
Data in XML | ![]() | 19.5 KB | Display | |
Data in CIF | ![]() | 30.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 38795MC ![]() 8xzfC ![]() 8xzhC ![]() 8xziC ![]() 8xzjC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 40414.047 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
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#2: Protein | Mass: 37285.734 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
#4: Protein/peptide | Mass: 1537.830 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#5: Protein | Mass: 42696.301 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() |
Has ligand of interest | N |
Has protein modification | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm |
Image recording | Electron dose: 62.4 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
EM software | Name: PHENIX / Category: model refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 2703505 | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 201936 / Symmetry type: POINT | ||||||||||||||||||||||||
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