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- PDB-9dzj: Human GC-A bound to ANP and 2xREGN5308 -

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Basic information

Entry
Database: PDB / ID: 9dzj
TitleHuman GC-A bound to ANP and 2xREGN5308
Components
  • (Atrial natriuretic ...) x 2
  • REGN5308 - Heavy chain
  • REGN5308 - Light chain
KeywordsMEMBRANE PROTEIN / receptor
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 speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsLiu, S. / Huang, X.-Y.
Funding support United States, 1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Aug 5, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Aug 5, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: REGN5308 - Heavy chain
L: REGN5308 - Light chain
G: REGN5308 - Heavy chain
K: REGN5308 - Light chain
A: Atrial natriuretic peptide receptor 1
B: Atrial natriuretic peptide receptor 1
C: Atrial natriuretic peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)333,78617
Polymers330,0787
Non-polymers3,70810
Water362
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Atrial natriuretic ... , 2 types, 3 molecules ABC

#3: Protein Atrial natriuretic peptide receptor 1 / Atrial natriuretic peptide receptor type A / ANP-A / ANPR-A / NPR-A / Guanylate cyclase A / GC-A


Mass: 115702.828 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPR1, ANPRA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P16066, guanylate cyclase
#4: Protein/peptide Atrial natriuretic peptide / ANP / Alpha-atrial natriuretic peptide / Alpha-hANP / Atrial natriuretic factor / ANF / CDD-ANF / ...ANP / Alpha-atrial natriuretic peptide / Alpha-hANP / Atrial natriuretic factor / ANF / CDD-ANF / CDD-ANP (99-126) / Cardionatrin / Pro atrial natriuretic factor 99-126 / proANF 99-126


Mass: 3087.505 Da / Num. of mol.: 1 / Fragment: UNP residues 124-151
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPPA, ANP, PND / Production host: Homo sapiens (human) / References: UniProt: P01160

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Antibody , 2 types, 4 molecules HGLK

#1: Antibody REGN5308 - Heavy chain


Mass: 24468.420 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#2: Antibody REGN5308 - Light chain


Mass: 23323.898 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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Sugars , 3 types, 8 molecules

#5: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#8: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 4 molecules

#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl / Feature type: SUBJECT OF INVESTIGATION
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: RGN5308 bound to NPR1-ANP / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 211000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00510432
ELECTRON MICROSCOPYf_angle_d0.62214245
ELECTRON MICROSCOPYf_dihedral_angle_d4.9971587
ELECTRON MICROSCOPYf_chiral_restr0.0741626
ELECTRON MICROSCOPYf_plane_restr0.0041800

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