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- EMDB-17578: SARS-CoV-2 S protein S:D614G mutant in 3-down with binding site o... -

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Basic information

Entry
Database: EMDB / ID: EMD-17578
TitleSARS-CoV-2 S protein S:D614G mutant in 3-down with binding site of an entry inhibitor
Map data
Sample
  • Complex: Spike glycoprotein - Severe acute respiratory syndrome coronavirus 2
    • Protein or peptide: Spike protein S1,Spike glycoprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: SODIUM ION
  • Ligand: [(2~{S})-2-[[4-(2-azanylethanoylamino)-7-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-4-[3-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-3-oxidanylidene-propyl]-7-oxidanylidene-heptanoyl]amino]-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]propanoyl]oxysodium
KeywordsSpike / SARS COV-2 / Inhibitor / VIRAL PROTEIN
Function / homology
Function and homology information


Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell ...Maturation of spike protein / viral translation / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular space / suppression by virus of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / entry receptor-mediated virion attachment to host cell / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / membrane fusion / receptor-mediated endocytosis of virus by host cell / Attachment and Entry / positive regulation of viral entry into host cell / receptor-mediated virion attachment to host cell / receptor ligand activity / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / virion attachment to host cell / SARS-CoV-2 activates/modulates innate and adaptive immune responses / host cell plasma membrane / virion membrane / identical protein binding / membrane / plasma membrane
Similarity search - Function
Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus ...Spike (S) protein S1 subunit, receptor-binding domain, SARS-CoV-2 / Spike (S) protein S1 subunit, N-terminal domain, SARS-CoV-like / Coronavirus spike glycoprotein S1, C-terminal / Coronavirus spike glycoprotein S1, C-terminal / Spike glycoprotein, betacoronavirus / Spike glycoprotein, N-terminal domain superfamily / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S2, coronavirus, heptad repeat 1 / Spike glycoprotein S2, coronavirus, heptad repeat 2 / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 1 (HR1) region profile. / Coronavirus spike (S) glycoprotein S2 subunit heptad repeat 2 (HR2) region profile. / Spike glycoprotein S2 superfamily, coronavirus / Spike glycoprotein S2, coronavirus / Coronavirus spike glycoprotein S2
Similarity search - Domain/homology
Biological speciesSevere acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsAdhav A / Forcada-Nadal A / Marco-Marin C / Lopez-Redondo ML / Llacer JL
Funding supportEuropean Union, Spain, 4 items
OrganizationGrant numberCountry
European CommissionEU 2020/2094European Union
Spanish Ministry of Science, Innovation, and UniversitiesPID2020 116880GB-I00 Spain
Spanish Ministry of Science, Innovation, and UniversitiesPID2020 120322RB-C21 Spain
Spanish National Research Council202080E110 Spain
CitationJournal: J Med Chem / Year: 2023
Title: C-2 Thiophenyl Tryptophan Trimers Inhibit Cellular Entry of SARS-CoV-2 through Interaction with the Viral Spike (S) Protein.
Authors: Marta Gargantilla / Clara Francés / Anmol Adhav / Alicia Forcada-Nadal / Belén Martínez-Gualda / Olaia Martí-Marí / María Luisa López-Redondo / Roberto Melero / Clara Marco-Marín / ...Authors: Marta Gargantilla / Clara Francés / Anmol Adhav / Alicia Forcada-Nadal / Belén Martínez-Gualda / Olaia Martí-Marí / María Luisa López-Redondo / Roberto Melero / Clara Marco-Marín / Nadine Gougeard / Carolina Espinosa / Antonio Rubio-Del-Campo / Rafael Ruiz-Partida / María Del Pilar Hernández-Sierra / Laura Villamayor-Belinchón / Jerónimo Bravo / José-Luis Llacer / Alberto Marina / Vicente Rubio / Ana San-Félix / Ron Geller / María-Jesús Pérez-Pérez /
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, by infecting cells via the interaction of its spike protein (S) with the primary cell receptor angiotensin-converting ...Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, by infecting cells via the interaction of its spike protein (S) with the primary cell receptor angiotensin-converting enzyme (ACE2). To search for inhibitors of this key step in viral infection, we screened an in-house library of multivalent tryptophan derivatives. Using VSV-S pseudoparticles, we identified compound as a potent entry inhibitor lacking cellular toxicity. Chemical optimization of rendered compounds and , which also potently inhibited genuine SARS-CoV-2 cell entry. Thermofluor and microscale thermophoresis studies revealed their binding to S and to its isolated receptor binding domain (RBD), interfering with the interaction with ACE2. High-resolution cryoelectron microscopy structure of S, free or bound to , shed light on cell entry inhibition mechanisms by these compounds. Overall, this work identifies and characterizes a new class of SARS-CoV-2 entry inhibitors with clear potential for preventing and/or fighting COVID-19.
History
DepositionJun 6, 2023-
Header (metadata) releaseSep 27, 2023-
Map releaseSep 27, 2023-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17578.png

Downloads & links

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Map

FileDownload / File: emd_17578.map.gz / Format: CCP4 / Size: 454.3 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.)
0.86 Å/pix.
x 492 pix.
= 420.66 Å		0.86 Å/pix.
x 492 pix.
= 420.66 Å		0.86 Å/pix.
x 492 pix.
= 420.66 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.855 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.01
Minimum - Maximum-0.0016816659 - 1.8666917
Average (Standard dev.)0.0010094047 (±0.022178778)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions492492492
Spacing492492492
CellA=B=C: 420.66 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_17578_half_map_1.map
Projections & Slices
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Density Histograms

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Half map: #1

Fileemd_17578_half_map_2.map
Projections & Slices
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Sample components

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Entire : Spike glycoprotein - Severe acute respiratory syndrome coronavirus 2

EntireName: Spike glycoprotein - Severe acute respiratory syndrome coronavirus 2
Components
  • Complex: Spike glycoprotein - Severe acute respiratory syndrome coronavirus 2
    • Protein or peptide: Spike protein S1,Spike glycoprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: SODIUM ION
  • Ligand: [(2~{S})-2-[[4-(2-azanylethanoylamino)-7-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-4-[3-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-3-oxidanylidene-propyl]-7-oxidanylidene-heptanoyl]amino]-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]propanoyl]oxysodium

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Supramolecule #1: Spike glycoprotein - Severe acute respiratory syndrome coronavirus 2

SupramoleculeName: Spike glycoprotein - Severe acute respiratory syndrome coronavirus 2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2

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Macromolecule #1: Spike protein S1,Spike glycoprotein

MacromoleculeName: Spike protein S1,Spike glycoprotein / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 140.904109 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MVSAIVLYVL LAAAAHSAFA CVNLTTRTQL PPAYTNSFTR GVYYPDKVFR SSVLHSTQDL FLPFFSNVTW FHAIHVSGTN GTKRFDNPV LPFNDGVYFA STEKSNIIRG WIFGTTLDSK TQSLLIVNNA TNVVIKVCEF QFCNDPFLGV YYHKNNKSWM E SEFRVYSS ...String:
MVSAIVLYVL LAAAAHSAFA CVNLTTRTQL PPAYTNSFTR GVYYPDKVFR SSVLHSTQDL FLPFFSNVTW FHAIHVSGTN GTKRFDNPV LPFNDGVYFA STEKSNIIRG WIFGTTLDSK TQSLLIVNNA TNVVIKVCEF QFCNDPFLGV YYHKNNKSWM E SEFRVYSS ANNCTFEYVS QPFLMDLEGK QGNFKNLREF VFKNIDGYFK IYSKHTPINL VRDLPQGFSA LEPLVDLPIG IN ITRFQTL LALHRSYLTP GDSSSGWTAG AAAYYVGYLQ PRTFLLKYNE NGTITDAVDC ALDPLSETKC TLKSFTVEKG IYQ TSNFRV QPTESIVRFP NITNLCPFGE VFNATRFASV YAWNRKRISN CVADYSVLYN SASFSTFKCY GVSPTKLNDL CFTN VYADS FVIRGDEVRQ IAPGQTGKIA DYNYKLPDDF TGCVIAWNSN NLDSKVGGNY NYLYRLFRKS NLKPFERDIS TEIYQ AGST PCNGVEGFNC YFPLQSYGFQ PTNGVGYQPY RVVVLSFELL HAPATVCGPK KSTNLVKNKC VNFNFNGLTG TGVLTE SNK KFLPFQQFGR DIADTTDAVR DPQTLEILDI TPCSFGGVSV ITPGTNTSNQ VAVLYQGVNC TEVPVAIHAD QLTPTWR VY STGSNVFQTR AGCLIGAEHV NNSYECDIPI GAGICASYQT QTNSPASVAS QSIIAYTMSL GAENSVAYSN NSIAIPTN F TISVTTEILP VSMTKTSVDC TMYICGDSTE CSNLLLQYGS FCTQLNRALT GIAVEQDKNT QEVFAQVKQI YKTPPIKDF GGFNFSQILP DPSKPSKRSF IEDLLFNKVT LADAGFIKQY GDCLGDIAAR DLICAQKFNG LTVLPPLLTD EMIAQYTSAL LAGTITSGW TFGAGAALQI PFAMQMAYRF NGIGVTQNVL YENQKLIANQ FNSAIGKIQD SLSSTASALG KLQDVVNQNA Q ALNTLVKQ LSSNFGAISS VLNDILSRLD PPEAEVQIDR LITGRLQSLQ TYVTQQLIRA AEIRASANLA ATKMSECVLG QS KRVDFCG KGYHLMSFPQ SAPHGVVFLH VTYVPAQEKN FTTAPAICHD GKAHFPREGV FVSNGTHWFV TQRNFYEPQI ITT DNTFVS GNCDVVIGIV NNTVYDPLQP ELDSFKEELD KYFKNHTSPD VDLGDISGIN ASVVNIQKEI DRLNEVAKNL NESL IDLQE LGKYEQYIKW PLVPRGSGYI PEAPRDGQAY VRKDGEWVFL STFLSPHHHH HHHHHEQKLI SEEDL

UniProtKB: Spike glycoprotein, Spike glycoprotein

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 24 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: SODIUM ION

MacromoleculeName: SODIUM ION / type: ligand / ID: 4 / Number of copies: 3
Molecular weightTheoretical: 22.99 Da

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Macromolecule #5: [(2~{S})-2-[[4-(2-azanylethanoylamino)-7-[[(2~{S})-3-[2-(4-nitrop...

MacromoleculeName: [(2~{S})-2-[[4-(2-azanylethanoylamino)-7-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-4-[3-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}- ...Name: [(2~{S})-2-[[4-(2-azanylethanoylamino)-7-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-4-[3-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-3-oxidanylidene-propyl]-7-oxidanylidene-heptanoyl]amino]-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]propanoyl]oxysodium
type: ligand / ID: 5 / Number of copies: 1 / Formula: XIO
Molecular weightTheoretical: 1.322402 KDa
Chemical component information

ChemComp-XIO:
[(2~{S})-2-[[4-(2-azanylethanoylamino)-7-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-4-[3-[[(2~{S})-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]-1-oxidanylidene-1-sodiooxy-propan-2-yl]amino]-3-oxidanylidene-propyl]-7-oxidanylidene-heptanoyl]amino]-3-[2-(4-nitrophenyl)sulfanyl-1~{H}-indol-3-yl]propanoyl]oxysodium

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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: 7.2 / Details: HEPES pH 7.2 150 mM NaCl
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 283.15 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 30.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

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

7qdg

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 97094
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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