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- EMDB-41234: Complex of NPR1 ectodomain and REGN5381 Fab in an active-like sta... -

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Basic information

Entry
Database: EMDB / ID: EMD-41234
TitleComplex of NPR1 ectodomain and REGN5381 Fab in an active-like state with no ANP bound
Map data
Sample
  • Complex: Active-like complex of NPR1 ectodomain and REGN5381 Fab, with no ANP present
    • Protein or peptide: Atrial natriuretic peptide receptor 1
    • Protein or peptide: REGN5381 Fab light chain
    • Protein or peptide: REGN5381 Fab heavy chain
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 / 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 / positive regulation of cGMP-mediated signaling / 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 / hormone binding / regulation of vascular permeability / positive regulation of urine volume / G protein-coupled peptide receptor activity / cGMP-mediated signaling / dopamine metabolic process / peptide hormone binding / negative regulation of angiogenesis / blood vessel diameter maintenance / negative regulation of smooth muscle cell proliferation / negative regulation of cell growth / regulation of blood pressure / receptor complex / cell surface receptor signaling pathway / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.65 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-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41234.png

Downloads & links

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Map

FileDownload / File: emd_41234.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: 0.107
Minimum - Maximum-0.37206116 - 0.88291705
Average (Standard dev.)-0.00017834394 (±0.019585166)
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_41234_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_41234_half_map_2.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Active-like complex of NPR1 ectodomain and REGN5381 Fab, with no ...

EntireName: Active-like complex of NPR1 ectodomain and REGN5381 Fab, with no ANP present
Components
  • Complex: Active-like complex of NPR1 ectodomain and REGN5381 Fab, with no ANP present
    • Protein or peptide: Atrial natriuretic peptide receptor 1
    • Protein or peptide: REGN5381 Fab light chain
    • Protein or peptide: REGN5381 Fab heavy chain

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Supramolecule #1: Active-like complex of NPR1 ectodomain and REGN5381 Fab, with no ...

SupramoleculeName: Active-like complex of NPR1 ectodomain and REGN5381 Fab, with no ANP present
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
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: REGN5381 Fab light chain

MacromoleculeName: REGN5381 Fab light chain / type: protein_or_peptide / ID: 2 / 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 #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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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: 41.0 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: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1312179
Startup modelType of model: NONE / Details: cryoSPARC ab initio model
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.65 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 495330
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 3

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