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- EMDB-61470: CMF-019 with APLNR-Gi complex -

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Basic information

Entry
Database: EMDB / ID: EMD-61470
TitleCMF-019 with APLNR-Gi complex
Map data
Sample
  • Complex: APLNR-bound CMF-019 in complex with Gi heterotrimer
    • Complex: APLNR in complex with Gi heterotrimer
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
      • Protein or peptide: Apelin receptor
    • Complex: scFv16
      • Protein or peptide: ScFv16
  • Ligand: (3~{S})-5-methyl-3-[[1-pentan-3-yl-2-(thiophen-2-ylmethyl)benzimidazol-5-yl]carbonylamino]hexanoic acid
KeywordsComplex / Agonist / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


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 / positive regulation of cardiac muscle hypertrophy in response to stress ...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 / positive regulation of cardiac muscle hypertrophy in response to stress / negative regulation of cAMP-mediated signaling / 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 / aorta development / negative regulation of cardiac muscle hypertrophy in response to stress / ventricular septum morphogenesis / blood vessel development / heart looping / vasculogenesis / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / gastrulation / cellular response to forskolin / regulation of mitotic spindle organization / positive regulation of release of sequestered calcium ion into cytosol / Peptide ligand-binding receptors / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / 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 / G beta:gamma signalling through BTK / positive regulation of angiogenesis / 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 / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / 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 complex adaptor activity / signaling receptor activity / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / heart development / regulation of gene expression / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / 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 / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway
Similarity search - Function
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. ...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 / 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
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
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.93 Å
AuthorsTian XW / Zhao C / Feng YY / Shao ZH / Sun JP
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31972916 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Multiscale biased chemical space remodeling for developing APLNR agonists with anti-HFpEF efficacy.
Authors: Qiu Sun / Xiaowen Tian / Lun Tan / Yan Deng / Sicen Liu / Yixiao Xiong / Yuying Feng / Yujia Wang / Lele Zhang / Jiayi Zhu / Huan Xiao / Zhenhua Shao / Yingqiang Guo / Wei Yan / Tao Li / Liang Ouyang /
Abstract: Heart failure with preserved ejection fraction (HFpEF) represents a significant global health burden, yet effective pharmacotherapies remain elusive. The angiotensin-like 1 receptor, also known as ...Heart failure with preserved ejection fraction (HFpEF) represents a significant global health burden, yet effective pharmacotherapies remain elusive. The angiotensin-like 1 receptor, also known as the apelin receptor (APLNR), is a promising target for treating HFpEF due to its role in modulating cardiovascular function. Despite the cardioprotective effects of endogenous ligand, apelin, achieving G-protein-biased agonism for therapeutic benefit poses a significant challenge. In this study, we unravel the biased signal transduction pathway mediated by a reported partial G-protein-biased APLNR agonist CMF-019 and developed a biased chemical space remodeling approach to identify exclusive G-protein-biased agonists targeting APLNR. These agonists exhibited enhanced Gi-protein-biased function and protective effects in both in vitro and in vivo. Our findings not only enhance comprehension of APLNR-biased agonism but also establish drug design strategies for modifying and reshaping biased chemical landscapes in other G-protein-coupled receptors (GPCRs).
History
DepositionSep 8, 2024-
Header (metadata) releaseApr 23, 2025-
Map releaseApr 23, 2025-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_61470.png

Downloads & links

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Map

FileDownload / File: emd_61470.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.375
Minimum - Maximum-2.5061684 - 3.583487
Average (Standard dev.)-0.004266549 (±0.09169231)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61470_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_61470_half_map_2.map
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Histogram (log scale)

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Sample components

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Entire : APLNR-bound CMF-019 in complex with Gi heterotrimer

EntireName: APLNR-bound CMF-019 in complex with Gi heterotrimer
Components
  • Complex: APLNR-bound CMF-019 in complex with Gi heterotrimer
    • Complex: APLNR in complex with Gi heterotrimer
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
      • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
      • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
      • Protein or peptide: Apelin receptor
    • Complex: scFv16
      • Protein or peptide: ScFv16
  • Ligand: (3~{S})-5-methyl-3-[[1-pentan-3-yl-2-(thiophen-2-ylmethyl)benzimidazol-5-yl]carbonylamino]hexanoic acid

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Supramolecule #1: APLNR-bound CMF-019 in complex with Gi heterotrimer

SupramoleculeName: APLNR-bound CMF-019 in complex with Gi heterotrimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #5, #2, #1, #4, #3

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Supramolecule #2: APLNR in complex with Gi heterotrimer

SupramoleculeName: APLNR in complex with Gi heterotrimer / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #5, #2, #1, #3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: scFv16

SupramoleculeName: scFv16 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.283836 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GCTLSAEDKA AVERSKMIDR NLREDGEKAA REVKLLLLGA GESGKSTIVK QMKIIHEAGY SEEECKQYKA VVYSNTIQSI IAIIRAMGR LKIDFGDSAR ADDARQLFVL AGAAEEGFMT AELAGVIKRL WKDSGVQACF NRSREYQLND SAAYYLNDLD R IAQPNYIP ...String:
GCTLSAEDKA AVERSKMIDR NLREDGEKAA REVKLLLLGA GESGKSTIVK QMKIIHEAGY SEEECKQYKA VVYSNTIQSI IAIIRAMGR LKIDFGDSAR ADDARQLFVL AGAAEEGFMT AELAGVIKRL WKDSGVQACF NRSREYQLND SAAYYLNDLD R IAQPNYIP TQQDVLRTRV KTTGIVETHF TFKDLHFKMF DVGGQRSERK KWIHCFEGVT AIIFCVALSD YDLVLAEDEE MN RMHESMK LFDSICNNKW FTDTSIILFL NKKDLFEEKI KKSPLTICYP EYAGSNTYEE AAAYIQCQFE DLNKRKDTKE IYT HFTCAT DTKNVQFVFD AVTDVIIKNN LKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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

MacromoleculeName: 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
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.342785 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Apelin receptor

MacromoleculeName: Apelin receptor / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.696301 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: 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

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Macromolecule #4: ScFv16

MacromoleculeName: ScFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 26.59466 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGSSDIVM TQATSSVPVT PGESVSISCR S SKSLLHSN ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS SGGGGSGGGG SGGGSSDIVM TQATSSVPVT PGESVSISCR S SKSLLHSN GNTYLYWFLQ RPGQSPQLLI YRMSNLASGV PDRFSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GA GTKLELK AAA

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Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.795876 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
TASIAQARKL VEQLKMEANI DRIKVSKAAA DLMAYCEAHA KEDPLLTPVP ASENPFREKK F

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #6: (3~{S})-5-methyl-3-[[1-pentan-3-yl-2-(thiophen-2-ylmethyl)benzimi...

MacromoleculeName: (3~{S})-5-methyl-3-[[1-pentan-3-yl-2-(thiophen-2-ylmethyl)benzimidazol-5-yl]carbonylamino]hexanoic acid
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1D5N
Molecular weightTheoretical: 455.613 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 55.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 593322
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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