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- EMDB-38971: The focused refinement map (Receptor) of CMF-019 bound APLNR-Gi1 ... -

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Basic information

Entry
Database: EMDB / ID: EMD-38971
TitleThe focused refinement map (Receptor) of CMF-019 bound APLNR-Gi1 structure.
Map data
Sample
  • Complex: CMF-019 bound APLNR complex.
    • Other: APLNR-CMF-019
KeywordsAPLNR / CMF-019 / STRUCTURAL PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsWang W / Ji S / Zhang Y
Funding support1 items
OrganizationGrant numberCountry
Not funded
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
DepositionFeb 2, 2024-
Header (metadata) releaseMar 20, 2024-
Map releaseMar 20, 2024-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38971.png

Downloads & links

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Map

FileDownload / File: emd_38971.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 224 pix.
= 184.576 Å		0.82 Å/pix.
x 224 pix.
= 184.576 Å		0.82 Å/pix.
x 224 pix.
= 184.576 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0141
Minimum - Maximum-0.044262897 - 0.070798784
Average (Standard dev.)-0.000033883643 (±0.001962592)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 184.576 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_38971_msk_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

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Half map: #1

Fileemd_38971_half_map_1.map
Projections & Slices
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Histogram

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Half map: #2

Fileemd_38971_half_map_2.map
Projections & Slices
AxesZYX

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Sample components

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Entire : CMF-019 bound APLNR complex.

EntireName: CMF-019 bound APLNR complex.
Components
  • Complex: CMF-019 bound APLNR complex.
    • Other: APLNR-CMF-019

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Supramolecule #1: CMF-019 bound APLNR complex.

SupramoleculeName: CMF-019 bound APLNR complex. / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: APLNR-CMF-019

MacromoleculeName: APLNR-CMF-019 / type: other / ID: 1 / Classification: other
SequenceString: MEEGGDFDNY YGADNQSECE YTDWKSSGAL IPAIYMLVFL LGTTGNGLVL WTVFRSSREK RRSADIFIAS LAVADLTFVV TLPLWATYTY RDYDWPFGTF FCKLSSYLIF VNMYASVFCL TGLSFDRYLA IVRPVANARL RLRVSGAVAT AVLWVLAALL AMPVMVLRTT ...String:
MEEGGDFDNY YGADNQSECE YTDWKSSGAL IPAIYMLVFL LGTTGNGLVL WTVFRSSREK RRSADIFIAS LAVADLTFVV TLPLWATYTY RDYDWPFGTF FCKLSSYLIF VNMYASVFCL TGLSFDRYLA IVRPVANARL RLRVSGAVAT AVLWVLAALL AMPVMVLRTT GDLENTTKVQ CYMDYSMVAT VSSEWAWEVG LGVSSTTVGF VVPFTIMLTC YFFIAQTIAG HFRKERIEGL RKRRRLLSII VVLVVTFALC WMPYHLVKTL YMLGSLLHWP CDFDLFLMNI FPYCTCISYV NSCLNPFLYA FFDPRFRQAC TSMLCCGQSR CAGTSHSSSG EKSASYSSGH SQGPGPNMGK GGEQMHEKSI PYSQETLVVD

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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: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 75660
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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