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- EMDB-43745: SARS-CoV-2 M protein dimer in complex with JNJ-9676 and Fab-B -

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Basic information

Entry
Database: EMDB / ID: EMD-43745
TitleSARS-CoV-2 M protein dimer in complex with JNJ-9676 and Fab-B
Map dataSARS-CoV-2 M protein dimer in complex with JNJ-9676 and Fab-B
Sample
  • Complex: Dimer complex of SARS-CoV-2 M protein with JNJ-9676 and Fab B
    • Protein or peptide: Membrane protein
    • Protein or peptide: Fab B Heavy Chain
    • Protein or peptide: Fab B Light Chain
  • Ligand: (6S,8R)-N-(3-cyanophenyl)-5-{4-[difluoro(phenyl)methyl]phenyl}-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide
KeywordsSARS-COV-2 / M protein / Inhibitor bound complex / VIRAL PROTEIN-Immune System complex
Function / homology
Function and homology information


Maturation of protein M / SARS-CoV-2 modulates autophagy / host cell Golgi membrane / CD28 dependent PI3K/Akt signaling / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / protein sequestering activity / VEGFR2 mediated vascular permeability / PIP3 activates AKT signaling / TRAF3-dependent IRF activation pathway ...Maturation of protein M / SARS-CoV-2 modulates autophagy / host cell Golgi membrane / CD28 dependent PI3K/Akt signaling / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / symbiont-mediated suppression of host cytoplasmic pattern recognition receptor signaling pathway via inhibition of MAVS activity / protein sequestering activity / VEGFR2 mediated vascular permeability / PIP3 activates AKT signaling / TRAF3-dependent IRF activation pathway / Translation of Structural Proteins / Virion Assembly and Release / Induction of Cell-Cell Fusion / structural constituent of virion / Attachment and Entry / viral envelope / SARS-CoV-2 activates/modulates innate and adaptive immune responses / virion membrane / identical protein binding / plasma membrane
Similarity search - Function
M matrix/glycoprotein, SARS-CoV-like / M matrix/glycoprotein, coronavirus / Coronavirus M matrix/glycoprotein / Coronavirus membrane (Cov-M) protein profile.
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / SARS-CoV-2 pseudovirus
Methodsingle particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsYin Y / Van Damme E
Funding support1 items
OrganizationGrant numberCountry
Other government0000-0003-1808-9851
CitationJournal: Nature / Year: 2025
Title: A small-molecule SARS-CoV-2 inhibitor targeting the membrane protein.
Authors: Ellen Van Damme / Pravien Abeywickrema / Yanting Yin / Jiexiong Xie / Sofie Jacobs / Mandeep Kaur Mann / Jordi Doijen / Robyn Miller / Madison Piassek / Simone Marsili / Murali Subramanian / ...Authors: Ellen Van Damme / Pravien Abeywickrema / Yanting Yin / Jiexiong Xie / Sofie Jacobs / Mandeep Kaur Mann / Jordi Doijen / Robyn Miller / Madison Piassek / Simone Marsili / Murali Subramanian / Leah Gottlieb / Rana Abdelnabi / Michiel Van Gool / Nick Van den Broeck / Ines De Pauw / Annick Diels / Peter Vermeulen / Koen Temmerman / Trevor Scobey / Melissa Mattocks / Alexandra Schäfer / Dirk Jochmans / Steven De Jonghe / Pieter Leyssen / Winston Chiu / Mayra Diosa Toro / Marleen Zwaagstra / Anouk A Leijs / Heidi L M De Gruyter / Christophe Buyck / Klaas Van Den Heede / Frank Jacobs / Christel Van den Eynde / Laura Thijs / Valerie Raeymaekers / Seth Miller / Amanda Del Rosario / Johan Neyts / Danielle Peeters / Ralph S Baric / Frank J M van Kuppeveld / Eric J Snijder / Martijn J van Hemert / Mario Monshouwer / Sujata Sharma / Ruxandra Draghia-Akli / Anil Koul / Marnix Van Loock /
Abstract: The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly. Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the ...The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly. Here we describe the identification of JNJ-9676, a small-molecule inhibitor targeting the coronavirus M protein. JNJ-9676 demonstrates in vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV and sarbecovirus strains from bat and pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), we determined a binding pocket of JNJ-9676 formed by the transmembrane domains of the M protein dimer. Compound binding stabilized the M protein dimer in an altered conformational state between its long and short forms, preventing the release of infectious virus. In a pre-exposure Syrian golden hamster model, JNJ-9676 (25 mg per kg twice per day) showed excellent efficacy, illustrated by a significant reduction in viral load and infectious virus in the lung by 3.5 and 4 log-transformed RNA copies and 50% tissue culture infective dose (TCID) per mg lung, respectively. Histopathology scores at this dose were reduced to the baseline. In a post-exposure hamster model, JNJ-9676 was efficacious at 75 mg per kg twice per day even when added at 48 h after infection, when peak viral loads were observed. The M protein is an attractive antiviral target to block coronavirus replication, and JNJ-9676 represents an interesting chemical series towards identifying clinical candidates addressing the current and future coronavirus pandemics.
History
DepositionFeb 20, 2024-
Header (metadata) releaseJan 29, 2025-
Map releaseJan 29, 2025-
UpdateApr 23, 2025-
Current statusApr 23, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43745.png

Downloads & links

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Map

FileDownload / File: emd_43745.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSARS-CoV-2 M protein dimer in complex with JNJ-9676 and Fab-B
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 320 pix.
= 291.2 Å		0.91 Å/pix.
x 320 pix.
= 291.2 Å		0.91 Å/pix.
x 320 pix.
= 291.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.156
Minimum - Maximum-1.1683683 - 1.7582474
Average (Standard dev.)-0.00007137959 (±0.0320704)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 291.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map B

Fileemd_43745_half_map_1.map
AnnotationHalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A

Fileemd_43745_half_map_2.map
AnnotationHalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Dimer complex of SARS-CoV-2 M protein with JNJ-9676 and Fab B

EntireName: Dimer complex of SARS-CoV-2 M protein with JNJ-9676 and Fab B
Components
  • Complex: Dimer complex of SARS-CoV-2 M protein with JNJ-9676 and Fab B
    • Protein or peptide: Membrane protein
    • Protein or peptide: Fab B Heavy Chain
    • Protein or peptide: Fab B Light Chain
  • Ligand: (6S,8R)-N-(3-cyanophenyl)-5-{4-[difluoro(phenyl)methyl]phenyl}-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

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Supramolecule #1: Dimer complex of SARS-CoV-2 M protein with JNJ-9676 and Fab B

SupramoleculeName: Dimer complex of SARS-CoV-2 M protein with JNJ-9676 and Fab B
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Membrane protein

MacromoleculeName: Membrane protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: SARS-CoV-2 pseudovirus
Molecular weightTheoretical: 29.977674 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADSNGTITV EELKKLLEQW NLVIGFLFLT WICLLQFAYA NRNRFLYIIK LIFLWLLWPV TLACFVLAAV YRINWITGGI AIAMACLVG LMWLSYFIAS FRLFARTRSM WSFNPETNIL LNVPLHGTIL TRPLLESELV IGAVILRGHL RIAGHHLGRC D IKDLPKEI ...String:
MADSNGTITV EELKKLLEQW NLVIGFLFLT WICLLQFAYA NRNRFLYIIK LIFLWLLWPV TLACFVLAAV YRINWITGGI AIAMACLVG LMWLSYFIAS FRLFARTRSM WSFNPETNIL LNVPLHGTIL TRPLLESELV IGAVILRGHL RIAGHHLGRC D IKDLPKEI TVATSRTLSY YKLGASQRVA GDSGFAAYSR YRIGNYKLNT DHSSSSDNIA LLVQSNSLEV LFQGPSRGGS GA AAGSGSG SGSPSRLEEE LRRRLTEGSE PEA

UniProtKB: Membrane protein

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Macromolecule #2: Fab B Heavy Chain

MacromoleculeName: Fab B Heavy Chain / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.157424 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: ASDIVMTQSP ASLAVSLGQR ATISCKASQS IDYDGDNYMN WYQQKPGQPP KLLIYTTSNL ESGIPARFSG SGSGTDFTLN IHPVEEGDA ATYYCQQNNE DPYTFGGGTK LEIKRADAAP TVSIFPPSSE QLTSGGASVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS ...String:
ASDIVMTQSP ASLAVSLGQR ATISCKASQS IDYDGDNYMN WYQQKPGQPP KLLIYTTSNL ESGIPARFSG SGSGTDFTLN IHPVEEGDA ATYYCQQNNE DPYTFGGGTK LEIKRADAAP TVSIFPPSSE QLTSGGASVV CFLNNFYPKD INVKWKIDGS E RQNGVLNS WTDQDSKDST YSMSSTLTLT KDEYERHNSY TCEATHKTST SPIVKSFNRN EC

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Macromolecule #3: Fab B Light Chain

MacromoleculeName: Fab B Light Chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.211092 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EVQLQQSGPE LVKPGASMKI SCKTSGYSFT GYTMNWVKQS HGKNLEWIGL INPYNGDTSY NQKFKGKATL TVDKSSSTAY MELLSLTSE DSAVYYCEVI NTYWGQGTLV TVSAAKTTPP SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP VTVTWNSGSL S SGVHTFPA ...String:
EVQLQQSGPE LVKPGASMKI SCKTSGYSFT GYTMNWVKQS HGKNLEWIGL INPYNGDTSY NQKFKGKATL TVDKSSSTAY MELLSLTSE DSAVYYCEVI NTYWGQGTLV TVSAAKTTPP SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP VTVTWNSGSL S SGVHTFPA VLQSDLYTLS SSVTVPSSTW PSETVTCNVA HPASSTKVDK KIVPRDCGSG SHHHHHH

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Macromolecule #4: (6S,8R)-N-(3-cyanophenyl)-5-{4-[difluoro(phenyl)methyl]phenyl}-6-...

MacromoleculeName: (6S,8R)-N-(3-cyanophenyl)-5-{4-[difluoro(phenyl)methyl]phenyl}-6-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide
type: ligand / ID: 4 / Number of copies: 2 / Formula: A1AE8
Molecular weightTheoretical: 497.495 Da

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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

BufferpH: 7.5
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 1.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DIFFRACTION / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7vgs

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 484616
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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