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- PDB-8tg9: Complex of NPR1 ectodomain with ANP plus an allosteric activating... -

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Basic information

Entry
Database: PDB / ID: 8tg9
TitleComplex of NPR1 ectodomain with ANP plus an allosteric activating antibody, REGN5381
Components
  • (Atrial natriuretic ...) x 2
  • (REGN5381 Fab ...) x 2
KeywordsIMMUNE SYSTEM / Atrial natriuretic peptide / antibody / activator / pulmonary hypertension
Function / homology
Function and homology information


: / ANPR-A receptor complex / natriuretic peptide receptor activity / positive regulation of cGMP-mediated signaling / neuropeptide receptor binding / body fluid secretion / regulation of high voltage-gated calcium channel activity / receptor guanylyl cyclase signaling pathway / positive regulation of potassium ion export across plasma membrane / peptide receptor activity ...: / ANPR-A receptor complex / natriuretic peptide receptor activity / positive regulation of cGMP-mediated signaling / neuropeptide receptor binding / body fluid secretion / regulation of high voltage-gated calcium channel activity / receptor guanylyl cyclase signaling pathway / positive regulation of potassium ion export across plasma membrane / peptide receptor activity / positive regulation of renal sodium excretion / guanylate cyclase / cGMP biosynthetic process / regulation of atrial cardiac muscle cell membrane repolarization / guanylate cyclase activity / Physiological factors / hormone binding / cardiac conduction system development / negative regulation of JUN kinase activity / YAP1- and WWTR1 (TAZ)-stimulated gene expression / sodium ion export across plasma membrane / regulation of vascular permeability / positive regulation of urine volume / neuropeptide hormone activity / hormone receptor binding / negative regulation of systemic arterial blood pressure / cardiac muscle hypertrophy in response to stress / G protein-coupled peptide receptor activity / aortic valve morphogenesis / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / cGMP-mediated signaling / dopamine metabolic process / peptide hormone binding / neuropeptide signaling pathway / positive regulation of heart rate / response to muscle stretch / positive regulation of cardiac muscle contraction / negative regulation of angiogenesis / blood vessel diameter maintenance / cell projection / female pregnancy / negative regulation of smooth muscle cell proliferation / negative regulation of cell growth / hormone activity / regulation of blood pressure / vasodilation / protein folding / : / perikaryon / receptor complex / cell surface receptor signaling pathway / protein kinase activity / Amyloid fiber formation / signaling receptor binding / GTP binding / protein-containing complex / extracellular space / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsFranklin, M.C. / Romero Hernandez, A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Nature / Year: 2024
Title: Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.
Authors: Michael E Dunn / Aaron Kithcart / Jee Hae Kim / Andre Jo-Hao Ho / Matthew C Franklin / Annabel Romero Hernandez / Jan de Hoon / Wouter Botermans / Jonathan Meyer / Ximei Jin / Dongqin Zhang ...Authors: Michael E Dunn / Aaron Kithcart / Jee Hae Kim / Andre Jo-Hao Ho / Matthew C Franklin / Annabel Romero Hernandez / Jan de Hoon / Wouter Botermans / Jonathan Meyer / Ximei Jin / Dongqin Zhang / Justin Torello / Daniel Jasewicz / Vishal Kamat / Elena Garnova / Nina Liu / Michael Rosconi / Hao Pan / Satyajit Karnik / Michael E Burczynski / Wenjun Zheng / Ashique Rafique / Jonas B Nielsen / Tanima De / Niek Verweij / Anita Pandit / Adam Locke / Naga Chalasani / Olle Melander / Tae-Hwi Schwantes-An / / Aris Baras / Luca A Lotta / Bret J Musser / Jason Mastaitis / Kishor B Devalaraja-Narashimha / Andrew J Rankin / Tammy Huang / Gary Herman / William Olson / Andrew J Murphy / George D Yancopoulos / Benjamin A Olenchock / Lori Morton /
Abstract: Heart failure is a leading cause of morbidity and mortality. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which ...Heart failure is a leading cause of morbidity and mortality. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.
History
DepositionJul 12, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 17, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Nov 20, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Atrial natriuretic peptide receptor 1
B: Atrial natriuretic peptide receptor 1
C: Atrial natriuretic peptide
H: REGN5381 Fab heavy chain
L: REGN5381 Fab light chain
E: REGN5381 Fab heavy chain
F: REGN5381 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)206,85113
Polymers203,9007
Non-polymers2,9516
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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

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


Mass: 52263.723 Da / Num. of mol.: 2 / Fragment: ectodomain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPR1, ANPRA / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P16066, guanylate cyclase
#2: 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 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01160

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Antibody , 2 types, 4 molecules HELF

#3: Antibody REGN5381 Fab heavy chain


Mass: 24818.770 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Strain: Velocimmune mouse / Production host: Cricetulus griseus (Chinese hamster)
#4: Antibody REGN5381 Fab 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) / Strain: Velocimmune mouse / Production host: Cricetulus griseus (Chinese hamster)

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Sugars , 4 types, 6 molecules

#5: 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-Glycam 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
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}}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
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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Details

Has ligand of interestN
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: Active complex of NPR1 ectodomain, ANP, and REGN5381 Fab
Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Cricetulus griseus (Chinese hamster)
Buffer solutionpH: 7.5
SpecimenConc.: 1.6 mg/ml / Embedding 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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
11cryoSPARCfinal Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1299989
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 682951 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 40.81 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.001714039
ELECTRON MICROSCOPYf_angle_d0.454919096
ELECTRON MICROSCOPYf_chiral_restr0.03932126
ELECTRON MICROSCOPYf_plane_restr0.00352450
ELECTRON MICROSCOPYf_dihedral_angle_d3.1872019

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