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- EMDB-41233: Complex of NPR1 ectodomain with ANP plus an allosteric activating... -

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Basic information

Entry
Database: EMDB / ID: EMD-41233
TitleComplex of NPR1 ectodomain with ANP plus an allosteric activating antibody, REGN5381
Map data
Sample
  • Complex: Active complex of NPR1 ectodomain, ANP, and REGN5381 Fab
    • Protein or peptide: Atrial natriuretic peptide receptor 1
    • Protein or peptide: Atrial natriuretic peptide
    • Protein or peptide: REGN5381 Fab heavy chain
    • Protein or peptide: REGN5381 Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsAtrial natriuretic peptide / antibody / activator / pulmonary hypertension / IMMUNE SYSTEM
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsFranklin MC / Romero Hernandez A
Funding support1 items
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, 2023-
Header (metadata) releaseJul 17, 2024-
Map releaseJul 17, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41233.png

Downloads & links

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Map

FileDownload / File: emd_41233.map.gz / Format: CCP4 / Size: 113.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 310 pix.
= 266.6 Å		0.86 Å/pix.
x 310 pix.
= 266.6 Å		0.86 Å/pix.
x 310 pix.
= 266.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.537
Minimum - Maximum-4.216814 - 6.196395
Average (Standard dev.)0.0017459996 (±0.14021935)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions310310310
Spacing310310310
CellA=B=C: 266.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_41233_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_41233_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 : Active complex of NPR1 ectodomain, ANP, and REGN5381 Fab

EntireName: Active complex of NPR1 ectodomain, ANP, and REGN5381 Fab
Components
  • Complex: Active complex of NPR1 ectodomain, ANP, and REGN5381 Fab
    • Protein or peptide: Atrial natriuretic peptide receptor 1
    • Protein or peptide: Atrial natriuretic peptide
    • Protein or peptide: REGN5381 Fab heavy chain
    • Protein or peptide: REGN5381 Fab light chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Active complex of NPR1 ectodomain, ANP, and REGN5381 Fab

SupramoleculeName: Active complex of NPR1 ectodomain, ANP, and REGN5381 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
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: 52.263723 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: GNLTVAVVLP LANTSYPWSW ARVGPAVELA LAQVKARPDL LPGWTVRTVL GSSENALGVC SDTAAPLAAV DLKWEHNPAV FLGPGCVYA AAPVGRFTAH WRVPLLTAGA PALGFGVKDE YALTTRAGPS YAKLGDFVAA LHRRLGWERQ ALMLYAYRPG D EEHCFFLV ...String:
GNLTVAVVLP LANTSYPWSW ARVGPAVELA LAQVKARPDL LPGWTVRTVL GSSENALGVC SDTAAPLAAV DLKWEHNPAV FLGPGCVYA AAPVGRFTAH WRVPLLTAGA PALGFGVKDE YALTTRAGPS YAKLGDFVAA LHRRLGWERQ ALMLYAYRPG D EEHCFFLV EGLFMRVRDR LNITVDHLEF AEDDLSHYTR LLRTMPRKGR VIYICSSPDA FRTLMLLALE AGLCGEDYVF FH LDIFGQS LQGGQGPAPR RPWERGDGQD VSARQAFQAA KIITYKDPDN PEYLEFLKQL KHLAYEQFNF TMEDGLVNTI PAS FHDGLL LYIQAVTETL AHGGTVTDGE NITQRMWNRS FQGVTGYLKI DSSGDRETDF SLWDMDPENG AFRVVLNYNG TSQE LVAVS GRKLNWPLGY PPPDIPKCGF DNEDPACNQD HLSTLEEQKL ISEEDLGGEQ KLISEEDLHH HHHH

UniProtKB: Atrial natriuretic peptide receptor 1

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Macromolecule #2: Atrial natriuretic peptide

MacromoleculeName: Atrial natriuretic peptide / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.087505 KDa
SequenceString:
SLRRSSCFGG RMDRIGAQSG LGCNSFRY

UniProtKB: Natriuretic peptides A

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Macromolecule #3: REGN5381 Fab heavy chain

MacromoleculeName: REGN5381 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse) / Strain: Velocimmune mouse
Molecular weightTheoretical: 24.81877 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: QVQLVQSGAE VKKPGASVTV SCKASGYTFT DYYMHWVRQA PGQGLEWMGW IKPNSGGTNS AQRFQGRITM TWDTSISTAY MELSRLRSD DTAVYYCSRG GPVMNYYYYY GMDVWGQGTT VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE P VTVSWNSG ...String:
QVQLVQSGAE VKKPGASVTV SCKASGYTFT DYYMHWVRQA PGQGLEWMGW IKPNSGGTNS AQRFQGRITM TWDTSISTAY MELSRLRSD DTAVYYCSRG GPVMNYYYYY GMDVWGQGTT VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTKTYTCN VDHKPSNTKV DKRVESKYGP P

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Macromolecule #4: REGN5381 Fab light chain

MacromoleculeName: REGN5381 Fab light chain / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse) / Strain: Velocimmune mouse
Molecular weightTheoretical: 23.323898 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
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 #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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.6 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1299989
Startup modelType of model: NONE / Details: cryoSPARC ab initio model
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 682951
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 6

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