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- EMDB-50035: SARS-CoV-2 M protein dimer (long form) in complex with Fab-E and ... -

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Basic information

Entry
Database: EMDB / ID: EMD-50035
TitleSARS-CoV-2 M protein dimer (long form) in complex with Fab-E and incubated with CIM-834
Map data
Sample
  • Complex: SARS-CoV-2 M protein dimer (long form) in complex with Fab-E and incubated with CIM-834
    • Protein or peptide: Membrane protein
    • Protein or peptide: Fab-E heavy chain
    • Protein or peptide: Fab-E light chain
KeywordsInhibitor / Complex / Membrane protein / Antibody / VIRAL PROTEIN
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 speciesSevere acute respiratory syndrome coronavirus 2 / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsDebski-Antoniak O / Hurdiss DL
Funding support Switzerland, Netherlands, 2 items
OrganizationGrant numberCountry
Innovative Medicines Initiative101005077 Switzerland
Netherlands Organisation for Scientific Research (NWO)184.034.014 Netherlands
CitationJournal: Nature / Year: 2025
Title: A coronavirus assembly inhibitor that targets the viral membrane protein.
Authors: Manon Laporte / Dirk Jochmans / Dorothée Bardiot / Lowiese Desmarets / Oliver J Debski-Antoniak / Giulia Mizzon / Rana Abdelnabi / Pieter Leyssen / Winston Chiu / Zhikuan Zhang / Norimichi ...Authors: Manon Laporte / Dirk Jochmans / Dorothée Bardiot / Lowiese Desmarets / Oliver J Debski-Antoniak / Giulia Mizzon / Rana Abdelnabi / Pieter Leyssen / Winston Chiu / Zhikuan Zhang / Norimichi Nomura / Sandro Boland / Umeharu Ohto / Yannick Stahl / Jurgen Wuyts / Steven De Jonghe / Annelies Stevaert / Martijn J van Hemert / Brenda W Bontes / Patrick Wanningen / G J Mirjam Groenewold / Aneta Zegar / Katarzyna Owczarek / Sanjata Joshi / Mohamed Koukni / Philippe Arzel / Hugo Klaassen / Jean-Christophe Vanherck / Ilse Vandecaetsbeek / Niels Cremers / Kim Donckers / Thibault Francken / Tina Van Buyten / Jasper Rymenants / Joost Schepers / Krzysztof Pyrc / Rolf Hilgenfeld / Jean Dubuisson / Berend-Jan Bosch / Frank Van Kuppeveld / Cecilia Eydoux / Etienne Decroly / Bruno Canard / Lieve Naesens / Birgit Weynand / Eric J Snijder / Sandrine Belouzard / Toshiyuki Shimizu / Ralf Bartenschlager / Daniel L Hurdiss / Arnaud Marchand / Patrick Chaltin / Johan Neyts /
Abstract: The coronavirus membrane protein (M) is the main organizer of coronavirus assembly. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained ...The coronavirus membrane protein (M) is the main organizer of coronavirus assembly. Here, we report on an M-targeting molecule, CIM-834, that blocks the assembly of SARS-CoV-2. CIM-834 was obtained through high-throughput phenotypic antiviral screening followed by medicinal-chemistry efforts and target elucidation. CIM-834 inhibits the replication of SARS-CoV-2 (including a broad panel of variants) and SARS-CoV. In SCID mice and Syrian hamsters intranasally infected with SARS-CoV-2, oral treatment reduced lung viral titres to nearly undetectable levels, even (as shown in mice) when treatment was delayed until 24 h before the end point. Treatment of infected hamsters prevented transmission to untreated sentinels. Transmission electron microscopy studies show that virion assembly is completely absent in cells treated with CIM-834. Single-particle cryo-electron microscopy reveals that CIM-834 binds and stabilizes the M protein in its short form, thereby preventing the conformational switch to the long form, which is required for successful particle assembly. In conclusion, we have discovered a new druggable target in the replication cycle of coronaviruses and a small molecule that potently inhibits it.
History
DepositionApr 5, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50035.png

Downloads & links

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Map

FileDownload / File: emd_50035.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 300 pix.
= 300.96 Å		1 Å/pix.
x 300 pix.
= 300.96 Å		1 Å/pix.
x 300 pix.
= 300.96 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0032 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.191
Minimum - Maximum-1.2075133 - 1.7884762
Average (Standard dev.)0.0008648367 (±0.030738022)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 300.96002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50035_msk_1.map
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Additional map: #1

Fileemd_50035_additional_1.map
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Half map: #1

Fileemd_50035_half_map_1.map
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Half map: #2

Fileemd_50035_half_map_2.map
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Sample components

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Entire : SARS-CoV-2 M protein dimer (long form) in complex with Fab-E and ...

EntireName: SARS-CoV-2 M protein dimer (long form) in complex with Fab-E and incubated with CIM-834
Components
  • Complex: SARS-CoV-2 M protein dimer (long form) in complex with Fab-E and incubated with CIM-834
    • Protein or peptide: Membrane protein
    • Protein or peptide: Fab-E heavy chain
    • Protein or peptide: Fab-E light chain

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Supramolecule #1: SARS-CoV-2 M protein dimer (long form) in complex with Fab-E and ...

SupramoleculeName: SARS-CoV-2 M protein dimer (long form) in complex with Fab-E and incubated with CIM-834
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 154 KDa

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Macromolecule #1: Membrane protein

MacromoleculeName: Membrane protein / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MHHHHHHHHD YKDDDDKENL YFQGMADSNG TITVEELKKL LEQWNLVIGF LFLTWICLLQ FAYANRNRFL YIIKLIFLWL LWPVTLACFV LAAVYRINWI TGGIAIAMAC LVGLMWLSYF IASFRLFART RSMWSFNPET NILLNVPLHG TILTRPLLES ELVIGAVILR ...String:
MHHHHHHHHD YKDDDDKENL YFQGMADSNG TITVEELKKL LEQWNLVIGF LFLTWICLLQ FAYANRNRFL YIIKLIFLWL LWPVTLACFV LAAVYRINWI TGGIAIAMAC LVGLMWLSYF IASFRLFART RSMWSFNPET NILLNVPLHG TILTRPLLES ELVIGAVILR GHLRIAGHHL GRCDIKDLPK EITVATSRTL SYYKLGASQR VAGDSGFAAY SRYRIGNYKL NTDHSSSSDN IALLVQ

UniProtKB: Membrane protein

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Macromolecule #2: Fab-E heavy chain

MacromoleculeName: Fab-E heavy chain / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: EVQLQQSGAE LVRPGSSVKI SCKGSGYVFS NYWMNWVKQR PGQGLEWIGQ IYPGDGDTNY NGKFKGKATL TADKSSSTAY MQLSSLTSED SAVYFCASGY LGENYVMDFW GQGTSVTVSS AKTTPPSVYP LAPGSAAQTN SMVTLGCLVK GYFPEPVTVT WNSGSLSSGV ...String:
EVQLQQSGAE LVRPGSSVKI SCKGSGYVFS NYWMNWVKQR PGQGLEWIGQ IYPGDGDTNY NGKFKGKATL TADKSSSTAY MQLSSLTSED SAVYFCASGY LGENYVMDFW GQGTSVTVSS AKTTPPSVYP LAPGSAAQTN SMVTLGCLVK GYFPEPVTVT WNSGSLSSGV HTFPAVLQSD LYTLSSSVTV PSSTWPSETV TCNVAHPASS TKVDKKIVPR DCGCKPCICT VPEVSS

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Macromolecule #3: Fab-E light chain

MacromoleculeName: Fab-E light chain / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Mus musculus (house mouse)
SequenceString: DIVLTQSPAS LTVSLGQRAT ISCRASESVD SFGNSFMHWY QQKPGQPPKL LIYRASNLES GIPARFSGSG SRTDFTLTIN PVEADDVATY YCQQSSEDPY TFGGGTKLEI KRADAAPTVS IFPPSSEQLT SGGASVVCFL NNFYPKDINV KWKIDGSERQ NGVLNSWTDQ ...String:
DIVLTQSPAS LTVSLGQRAT ISCRASESVD SFGNSFMHWY QQKPGQPPKL LIYRASNLES GIPARFSGSG SRTDFTLTIN PVEADDVATY YCQQSSEDPY TFGGGTKLEI KRADAAPTVS IFPPSSEQLT SGGASVVCFL NNFYPKDINV KWKIDGSERQ NGVLNSWTDQ DSKDSTYSMS STLTLTKDEY ERHNSYTCEA THKTSTSPIV KSFNRNEC

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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: 7.7
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 5058 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 81000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 4325852
Startup modelType of model: NONE / Details: ab initio
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 78081
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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