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- PDB-8tga: Complex of NPR1 ectodomain and REGN5381 Fab in an active-like sta... -

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Basic information

Entry
Database: PDB / ID: 8tga
TitleComplex of NPR1 ectodomain and REGN5381 Fab in an active-like state with no ANP bound
Components
  • Atrial natriuretic peptide receptor 1
  • REGN5381 Fab heavy chain
  • REGN5381 Fab light chain
KeywordsIMMUNE SYSTEM / Atrial natriuretic peptide / antibody / activator / pulmonary hypertension
Function / homology
Function and homology information


ANPR-A receptor complex / natriuretic peptide receptor activity / : / body fluid secretion / receptor guanylyl cyclase signaling pathway / peptide receptor activity / positive regulation of renal sodium excretion / guanylate cyclase / cGMP biosynthetic process / guanylate cyclase activity ...ANPR-A receptor complex / natriuretic peptide receptor activity / : / body fluid secretion / receptor guanylyl cyclase signaling pathway / peptide receptor activity / positive regulation of renal sodium excretion / guanylate cyclase / cGMP biosynthetic process / guanylate cyclase activity / Physiological factors / regulation of vascular permeability / positive regulation of urine volume / G protein-coupled peptide receptor activity / : / dopamine metabolic process / hormone binding / peptide hormone binding / blood vessel diameter maintenance / negative regulation of angiogenesis / negative regulation of smooth muscle cell proliferation / negative regulation of cell growth / regulation of blood pressure / cell surface receptor signaling pathway / receptor complex / protein kinase activity / 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 / 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
Atrial natriuretic peptide receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.65 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 16, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
Revision 1.2Oct 30, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)200,8136
Polymers200,8136
Non-polymers00
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

#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: 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)
#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)
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-like complex of NPR1 ectodomain and REGN5381 Fab, with no ANP present
Type: COMPLEX / Entity ID: all / 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: 1000 nm
Image recordingElectron dose: 41 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: 1312179
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 495330 / Symmetry type: POINT
RefinementCross valid method: NONE

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