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- EMDB-47331: Human GC-A bound to ANP and 2xREGN5308 -

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Basic information

Entry
Database: EMDB / ID: EMD-47331
TitleHuman GC-A bound to ANP and 2xREGN5308
Map data
Sample
  • Complex: RGN5308 bound to NPR1-ANP
    • Protein or peptide: REGN5308 - Heavy chain
    • Protein or peptide: REGN5308 - Light chain
    • Protein or peptide: Atrial natriuretic peptide receptor 1
    • Protein or peptide: Atrial natriuretic peptide
  • Ligand: CHLORIDE ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water
Keywordsreceptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of collecting lymphatic vessel constriction / body fluid secretion / natriuretic peptide receptor activity / cell growth involved in cardiac muscle cell development / neuropeptide receptor binding / mast cell granule / response to 3-methylcholanthrene / peptide receptor activity / positive regulation of potassium ion export across plasma membrane / guanylate cyclase ...negative regulation of collecting lymphatic vessel constriction / body fluid secretion / natriuretic peptide receptor activity / cell growth involved in cardiac muscle cell development / neuropeptide receptor binding / mast cell granule / response to 3-methylcholanthrene / peptide receptor activity / positive regulation of potassium ion export across plasma membrane / guanylate cyclase / receptor guanylyl cyclase signaling pathway / guanylate cyclase activity / negative regulation of JUN kinase activity / synaptic signaling via neuropeptide / regulation of atrial cardiac muscle cell membrane repolarization / cGMP biosynthetic process / Physiological factors / cardiac conduction system development / positive regulation of renal sodium excretion / YAP1- and WWTR1 (TAZ)-stimulated gene expression / neuropeptide hormone activity / hormone receptor binding / regulation of vascular permeability / glycinergic synapse / G protein-coupled peptide receptor activity / negative regulation of systemic arterial blood pressure / aortic valve morphogenesis / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of urine volume / dopamine metabolic process / cellular response to angiotensin / peptide hormone binding / hormone binding / brush border / response to muscle stretch / positive regulation of heart rate / cell projection / positive regulation of cardiac muscle contraction / negative regulation of angiogenesis / blood vessel diameter maintenance / negative regulation of smooth muscle cell proliferation / cellular response to glucose stimulus / female pregnancy / neuropeptide signaling pathway / cellular response to mechanical stimulus / response to insulin / hormone activity / negative regulation of cell growth / vasodilation / regulation of blood pressure / cellular response to hydrogen peroxide / nuclear membrane / protein folding / response to hypoxia / perikaryon / protein kinase activity / signaling receptor complex / cell surface receptor signaling pathway / intracellular signal transduction / Amyloid fiber formation / signaling receptor binding / endoplasmic reticulum membrane / GTP binding / perinuclear region of cytoplasm / protein-containing complex / : / extracellular region / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
Natriuretic peptide, atrial type / : / Natriuretic peptide, conserved site / Atrial natriuretic peptide / Natriuretic peptides signature. / Natriuretic peptide / Natriuretic peptide / Adenylyl cyclase class-4/guanylyl cyclase / Natriuretic peptides receptors signature. / : ...Natriuretic peptide, atrial type / : / Natriuretic peptide, conserved site / Atrial natriuretic peptide / Natriuretic peptides signature. / Natriuretic peptide / Natriuretic peptide / 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
Natriuretic peptides A / Atrial natriuretic peptide receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 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_47331.png

Downloads & links

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Map

FileDownload / File: emd_47331.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
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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

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-4.3465385 - 6.769871
Average (Standard dev.)0.00027235204 (±0.16369677)
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_47331_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_47331_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : RGN5308 bound to NPR1-ANP

EntireName: RGN5308 bound to NPR1-ANP
Components
  • Complex: RGN5308 bound to NPR1-ANP
    • Protein or peptide: REGN5308 - Heavy chain
    • Protein or peptide: REGN5308 - Light chain
    • Protein or peptide: Atrial natriuretic peptide receptor 1
    • Protein or peptide: Atrial natriuretic peptide
  • Ligand: CHLORIDE ION
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water

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Supramolecule #1: RGN5308 bound to NPR1-ANP

SupramoleculeName: RGN5308 bound to NPR1-ANP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: REGN5308 - Heavy chain

MacromoleculeName: REGN5308 - Heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 2 / 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 #2: REGN5308 - Light chain

MacromoleculeName: REGN5308 - Light chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / 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 #3: Atrial natriuretic peptide receptor 1

MacromoleculeName: Atrial natriuretic peptide receptor 1 / type: protein_or_peptide / ID: 3 / 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 #4: Atrial natriuretic peptide

MacromoleculeName: Atrial natriuretic peptide / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.087505 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
SLRRSSCFGG RMDRIGAQSG LGCNSFRY

UniProtKB: Natriuretic peptides A

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Macromolecule #7: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 7 / Number of copies: 2 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #9: water

MacromoleculeName: water / type: ligand / ID: 9 / Number of copies: 2 / 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: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 211000
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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