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- EMDB-47332: Human GC-A bound to REGN5308 -

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Basic information

Entry
Database: EMDB / ID: EMD-47332
TitleHuman GC-A bound to REGN5308
Map data
Sample
  • Complex: Complex of Guanylyl Cyclase-A/Natriuretic peptide receptor A with Fab fragment
    • Protein or peptide: Atrial natriuretic peptide receptor 1
    • Protein or peptide: REGN5308 - Heavy chain
    • Protein or peptide: REGN5308 - Light chain
  • Ligand: CHLORIDE ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water
Keywordsreceptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


body fluid secretion / natriuretic peptide receptor activity / peptide receptor activity / guanylate cyclase / receptor guanylyl cyclase signaling pathway / guanylate cyclase activity / cGMP biosynthetic process / Physiological factors / positive regulation of renal sodium excretion / regulation of vascular permeability ...body fluid secretion / natriuretic peptide receptor activity / peptide receptor activity / guanylate cyclase / receptor guanylyl cyclase signaling pathway / guanylate cyclase activity / cGMP biosynthetic process / Physiological factors / positive regulation of renal sodium excretion / regulation of vascular permeability / G protein-coupled peptide receptor activity / positive regulation of urine volume / dopamine metabolic process / peptide hormone binding / hormone binding / negative regulation of angiogenesis / blood vessel diameter maintenance / negative regulation of smooth muscle cell proliferation / negative regulation of cell growth / regulation of blood pressure / nuclear membrane / protein kinase activity / signaling receptor complex / cell surface receptor signaling pathway / intracellular signal transduction / endoplasmic reticulum membrane / GTP binding / ATP binding / plasma membrane
Similarity search - Function
Adenylyl cyclase class-4/guanylyl cyclase / Natriuretic peptides receptors signature. / : / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylate and Guanylate cyclase catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Guanylate cyclase domain profile. / Nucleotide cyclase ...Adenylyl cyclase class-4/guanylyl cyclase / Natriuretic peptides receptors signature. / : / Adenylyl cyclase class-4/guanylyl cyclase, conserved site / Guanylate cyclase signature. / Adenylyl- / guanylyl cyclase, catalytic domain / Adenylate and Guanylate cyclase catalytic domain / Adenylyl cyclase class-3/4/guanylyl cyclase / Guanylate cyclase domain profile. / Nucleotide cyclase / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Atrial natriuretic peptide receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsLiu S / Huang X-Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Nat Commun / Year: 2026
Title: Structural insights into single-pass transmembrane receptor GC-A activation by distinct antihypertensive antibodies.
Authors: Shian Liu / Onorina Manzo / Jinan Wang / Lan Zhu / Fu Xiao / Yi-Chen Su / Devanshu Kurre / Wei Liu / Yinglong Miao / Annarita Di Lorenzo / Xin-Yun Huang /
Abstract: The single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor A (NPR-A) or NPR1, regulates blood pressure through vasodilation and natriuresis, making ...The single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor A (NPR-A) or NPR1, regulates blood pressure through vasodilation and natriuresis, making it a promising therapeutic target for hypertension and heart failure. We describe two monoclonal antibodies, XX16 and REGN5308, that differentially activate GC-A. Using cryo-electron microscopy and molecular dynamics simulations, we reveal that XX16 stabilizes GC-A in an active conformation even without its ligand ANP, whereas REGN5308 requires ANP to fully promote receptor activation. Both antibodies increase ANP binding affinity to GC-A and enhance GC-A-mediated cGMP signaling, although XX16 exerts a stronger stabilizing influence on ATP and GTP binding. In a mouse model of obesity-induced hypertension, XX16 treatment significantly reduces blood pressure, underscoring its therapeutic potential. These findings outline the structural and functional basis of GC-A activation by antibody positive allosteric modulators, offering strategies for durable antihypertensive therapies and improved management of cardiovascular diseases.
History
DepositionOct 16, 2024-
Header (metadata) releaseJan 21, 2026-
Map releaseJan 21, 2026-
UpdateAug 5, 2026-
Current statusAug 5, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47332.png

Downloads & links

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Map

FileDownload / File: emd_47332.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å		1.07 Å/pix.
x 256 pix.
= 273.92 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.8
Minimum - Maximum-5.037984 - 6.653326
Average (Standard dev.)0.0005923672 (±0.11670706)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 273.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_47332_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_47332_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of Guanylyl Cyclase-A/Natriuretic peptide receptor A with...

EntireName: Complex of Guanylyl Cyclase-A/Natriuretic peptide receptor A with Fab fragment
Components
  • Complex: Complex of Guanylyl Cyclase-A/Natriuretic peptide receptor A with Fab fragment
    • Protein or peptide: Atrial natriuretic peptide receptor 1
    • Protein or peptide: REGN5308 - Heavy chain
    • Protein or peptide: REGN5308 - Light chain
  • Ligand: CHLORIDE ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water

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Supramolecule #1: Complex of Guanylyl Cyclase-A/Natriuretic peptide receptor A with...

SupramoleculeName: Complex of Guanylyl Cyclase-A/Natriuretic peptide receptor A with Fab fragment
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Atrial natriuretic peptide receptor 1

MacromoleculeName: Atrial natriuretic peptide receptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: guanylate cyclase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 115.702828 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: AAGNLTVAVV LPLANTSYPW SWARVGPAVE LALAQVKARP DLLPGWTVRT VLGSSENALG VCSDTAAPLA AVDLKWEHNP AVFLGPGCV YAAAPVGRFT AHWRVPLLTA GAPALGFGVK DEYALTTRAG PSYAKLGDFV AALHRRLGWE RQALMLYAYR P GDEEHCFF ...String:
AAGNLTVAVV LPLANTSYPW SWARVGPAVE LALAQVKARP DLLPGWTVRT VLGSSENALG VCSDTAAPLA AVDLKWEHNP AVFLGPGCV YAAAPVGRFT AHWRVPLLTA GAPALGFGVK DEYALTTRAG PSYAKLGDFV AALHRRLGWE RQALMLYAYR P GDEEHCFF LVEGLFMRVR DRLNITVDHL EFAEDDLSHY TRLLRTMPRK GRVIYICSSP DAFRTLMLLA LEAGLCGEDY VF FHLDIFG QSLQGGQGPA PRRPWERGDG QDVSARQAFQ AAKIITYKDP DNPEYLEFLK QLKHLAYEQF NFTMEDGLVN TIP ASFHDG LLLYIQAVTE TLAHGGTVTD GENITQRMWN RSFQGVTGYL KIDSSGDRET DFSLWDMDPE NGAFRVVLNY NGTS QELVA VSGRKLNWPL GYPPPDIPKC GFDNEDPACN QDHLSTLEVL ALVGSLSLLG ILIVSFFIYR KMQLEKELAS ELWRV RWED VEPSSLERHL RSAGSRLTLS GRGSNYGSLL TTEGQFQVFA KTAYYKGNLV AVKRVNRKRI ELTRKVLFEL KHMRDV QNE HLTRFVGACT DPPNICILTE YCPRGSLQDI LENESITLDW MFRYSLTNDI VKGMLFLHNG AICSHGNLKS SNCVVDG RF VLKITDYGLE SFRDLDPEQG HTVYAKKLWT APELLRMASP PVRGSQAGDV YSFGIILQEI ALRSGVFHVE GLDLSPKE I IERVTRGEQP PFRPSLALQS HLEELGLLMQ RCWAEDPQER PPFQQIRLTL RKFNRENSSN ILDNLLSRME QYANNLEEL VEERTQAYLE EKRKAEALLY QILPHSVAEQ LKRGETVQAE AFDSVTIYFS DIVGFTALSA ESTPMQVVTL LNDLYTCFDA VIDNFDVYK VETIGDAYMV VSGLPVRNGR LHACEVARMA LALLDAVRSF RIRHRPQEQL RLRIGIHTGP VCAGVVGLKM P RYCLFGDT VNTASRMESN GEALKIHLSS ETKAVLEEFG GFELELRGDV EMKGKGKVRT YWLLGERGSS TRG

UniProtKB: Atrial natriuretic peptide receptor 1

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Macromolecule #2: REGN5308 - Heavy chain

MacromoleculeName: REGN5308 - Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.46842 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: QVQLVQSGAE VKKPGASVTV SCKASGYTFT DYYMHWVRQA PGQGLEWMGW IKPNSGGTNS AQRFQGRITM TWDTSISTAY MELSRLRSD DTAVYYCSRG GPVMNYYYYY GMDVWGQGTT VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
QVQLVQSGAE VKKPGASVTV SCKASGYTFT DYYMHWVRQA PGQGLEWMGW IKPNSGGTNS AQRFQGRITM TWDTSISTAY MELSRLRSD DTAVYYCSRG GPVMNYYYYY GMDVWGQGTT VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKRVEPKSC

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Macromolecule #3: REGN5308 - Light chain

MacromoleculeName: REGN5308 - Light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.323898 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: NIQMTQSPSS LSASVGDRVT ITCRASQSID SYLNWYQQKP GKAPKLLIYV ASSLQSGVPS RFSGSGSGKD FTLTISSLQP EDFATYYCQ QSYSIPTFGQ GTRLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String:
NIQMTQSPSS LSASVGDRVT ITCRASQSID SYLNWYQQKP GKAPKLLIYV ASSLQSGVPS RFSGSGSGKD FTLTISSLQP EDFATYYCQ QSYSIPTFGQ GTRLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC

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Macromolecule #6: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 6 / Number of copies: 2 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #8: water

MacromoleculeName: water / type: ligand / ID: 8 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k 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: 2.0 µm / Nominal defocus min: 0.8 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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 291000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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