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- PDB-8w2e: SARS-CoV-2 M protein dimer in complex with JNJ-9676 and Fab-B -

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Basic information

Entry
Database: PDB / ID: 8w2e
TitleSARS-CoV-2 M protein dimer in complex with JNJ-9676 and Fab-B
Components
  • Fab B Heavy Chain
  • Fab B Light Chain
  • Membrane protein
KeywordsVIRAL PROTEIN/Immune System / SARS-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
: / Membrane protein
Similarity search - Component
Biological speciesSARS-CoV-2 pseudovirus
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsYin, Y. / Van Damme, E.
Funding support1items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1Apr 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_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Apr 23, 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 Heavy Chain
D: Fab B Light Chain
E: Fab B Heavy Chain
F: Fab B Light Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)157,6878
Polymers156,6926
Non-polymers9952
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 29977.674 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) SARS-CoV-2 pseudovirus / Production host: Homo sapiens (human) / References: UniProt: P0DTC5
#2: Antibody Fab B Heavy Chain


Mass: 24157.424 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Antibody Fab B Light Chain


Mass: 24211.092 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#4: Chemical ChemComp-A1AE8 / (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


Mass: 497.495 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H21F2N5O2 / 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: Dimer complex of SARS-CoV-2 M protein with JNJ-9676 and Fab B
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: NITROGEN

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DIFFRACTION / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 1 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 484616 / Symmetry type: POINT

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