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Yorodumi- EMDB-38795: Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-38795 | |||||||||
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Title | Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | APLNR / apelin / Class A GPCR / Structural protein / MEMBRANE PROTEIN | |||||||||
Function / homology | Function and homology information apelin receptor binding / positive regulation of G protein-coupled receptor internalization / apelin receptor activity / apelin receptor signaling pathway / regulation of gap junction assembly / positive regulation of inhibitory G protein-coupled receptor phosphorylation / vascular associated smooth muscle cell differentiation / atrioventricular valve development / regulation of body fluid levels / venous blood vessel development ...apelin receptor binding / positive regulation of G protein-coupled receptor internalization / apelin receptor activity / apelin receptor signaling pathway / regulation of gap junction assembly / positive regulation of inhibitory G protein-coupled receptor phosphorylation / 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 / drinking behavior / positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / endocardial cushion formation / adult heart development / coronary vasculature development / vasculature development / negative regulation of cAMP-mediated signaling / aorta development / positive regulation of vascular endothelial cell proliferation / ventricular septum morphogenesis / heart looping / blood vessel development / negative regulation of vascular associated smooth muscle cell proliferation / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / gastrulation / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / vasculogenesis / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / negative regulation of blood pressure / lactation / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / 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 / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / hormone activity / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to peptide hormone / 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 / positive regulation of miRNA transcription / 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 / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / positive regulation of angiogenesis / 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 / signaling receptor activity / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / heart development / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / regulation of gene expression Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
Authors | Wang W / Ji S / Zhang Y | |||||||||
Funding support | China, 2 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_38795.map.gz | 17.9 MB | EMDB map data format | |
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Header (meta data) | emd-38795-v30.xml emd-38795.xml | 19.4 KB 19.4 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_38795_fsc.xml | 8.8 KB | Display | FSC data file |
Images | emd_38795.png | 49.8 KB | ||
Masks | emd_38795_msk_1.map | 27 MB | Mask map | |
Filedesc metadata | emd-38795.cif.gz | 6.4 KB | ||
Others | emd_38795_half_map_1.map.gz emd_38795_half_map_2.map.gz | 20.7 MB 20.7 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-38795 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-38795 | HTTPS FTP |
-Related structure data
Related structure data | 8xzgMC 8xzfC 8xzhC 8xziC 8xzjC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_38795.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.014 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_38795_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_38795_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_38795_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex
Entire | Name: Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex |
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Components |
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-Supramolecule #1: Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex
Supramolecule | Name: Cryo-EM structure of the [Pyr1]-apelin-13-bound human APLNR-Gi complex type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 40.414047 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-Macromolecule #2: 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: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 37.285734 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW ...String: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NAICFFPNGN AF ATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGHDNRVSCL GVT DDGMAV ATGSWDSFLK IWN UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #4: Apelin-13
Macromolecule | Name: Apelin-13 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 1.53783 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
Sequence | String: (PCA)RPRLSHKGP MPF UniProtKB: Apelin |
-Macromolecule #5: Apelin receptor
Macromolecule | Name: Apelin receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 42.696301 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MEEGGDFDNY YGADNQSECE YTDWKSSGAL IPAIYMLVFL LGTTGNGLVL WTVFRSSREK RRSADIFIAS LAVADLTFVV TLPLWATYT YRDYDWPFGT FFCKLSSYLI FVNMYASVFC LTGLSFDRYL AIVRPVANAR LRLRVSGAVA TAVLWVLAAL L AMPVMVLR ...String: MEEGGDFDNY YGADNQSECE YTDWKSSGAL IPAIYMLVFL LGTTGNGLVL WTVFRSSREK RRSADIFIAS LAVADLTFVV TLPLWATYT YRDYDWPFGT FFCKLSSYLI FVNMYASVFC LTGLSFDRYL AIVRPVANAR LRLRVSGAVA TAVLWVLAAL L AMPVMVLR TTGDLENTTK VQCYMDYSMV ATVSSEWAWE VGLGVSSTTV GFVVPFTIML TCYFFIAQTI AGHFRKERIE GL RKRRRLL SIIVVLVVTF ALCWMPYHLV KTLYMLGSLL HWPCDFDLFL MNIFPYCTCI SYVNSCLNPF LYAFFDPRFR QAC TSMLCC GQSRCAGTSH SSSGEKSASY SSGHSQGPGP NMGKGGEQMH EKSIPYSQET LVVD UniProtKB: Apelin receptor |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 15 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 62.4 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |