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- PDB-9exa: SARS-CoV-2 M protein dimer (short form) in complex with Fab-B and... -

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Basic information

Entry
Database: PDB / ID: 9exa
TitleSARS-CoV-2 M protein dimer (short form) in complex with Fab-B and CIM-834
Components
  • Fab-B heavy chain
  • Fab-B light chain
  • Membrane protein
KeywordsVIRAL PROTEIN / Inhibitor / Complex / Membrane protein / Antibody
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
: / Membrane protein
Similarity search - Component
Biological speciesSevere acute respiratory syndrome coronavirus 2
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsDebski-Antoniak, O.J. / Hurdiss, D.L.
Funding support Switzerland, Netherlands, 2items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 2, 2025Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.pdbx_database_id_DOI / _citation.title ..._citation.pdbx_database_id_DOI / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Apr 9, 2025Group: 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.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.3Apr 16, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Membrane protein
B: Membrane protein
C: Fab-B light chain
D: Fab-B heavy chain
E: Fab-B light chain
F: Fab-B heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)137,7668
Polymers136,7776
Non-polymers9892
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area16750 Å2
ΔGint-90 kcal/mol
Surface area51590 Å2
MethodPISA

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Components

#1: Protein Membrane protein / M / E1 glycoprotein / Matrix glycoprotein / Membrane glycoprotein


Mass: 21513.469 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Severe acute respiratory syndrome coronavirus 2
Cell line (production host): Expi293F cells / Production host: Homo sapiens (human) / References: UniProt: P0DTC5
#2: Antibody Fab-B light chain


Mass: 23999.266 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): TIB-18 / Production host: Mus musculus (house mouse)
#3: Antibody Fab-B heavy chain


Mass: 22875.719 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): TIB-18 / Production host: Mus musculus (house mouse)
#4: Chemical ChemComp-A1H7W / 6-[[1-[4,6-dimethyl-5-(2-methylpropyl)pyrimidin-2-yl]piperidin-4-yl]-methyl-amino]-N-(2-pyrrolidin-1-ylethyl)pyridazine-4-carboxamide


Mass: 494.675 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H42N8O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
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: SARS-CoV-2 M protein dimer (short form) in complex with Fab-B and CIM-834
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.154 MDa / Experimental value: NO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Source (recombinant)Organism: Homo sapiens (human) / Cell: Expi293F cells
Buffer solutionpH: 7.7
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameCategory
4cryoSPARCCTF correction
7UCSF Chimeramodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4497785
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 72998 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model building

3D fitting-ID: 1

IDPDB-IDAccession codeInitial refinement model-IDSource nameTypeDetails
18CTK

8ctk

8CTK1PDBexperimental model
2AlphaFoldin silico modelFab-B
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049948
ELECTRON MICROSCOPYf_angle_d0.49313562
ELECTRON MICROSCOPYf_dihedral_angle_d7.2091380
ELECTRON MICROSCOPYf_chiral_restr0.0411526
ELECTRON MICROSCOPYf_plane_restr0.0041704

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