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- EMDB-75697: SARS-CoV-2 spike S2 trimer stabilized in the early fusion interme... -

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Basic information

Entry
Database: EMDB / ID: EMD-75697
TitleSARS-CoV-2 spike S2 trimer stabilized in the early fusion intermediate conformation (E-FICs-v3) bound to C77G12 (S2 local refinement)
Map data
Sample
  • Complex: SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate conformation by circular permutation and clamping by modified EIAV gp45m plus C77G12 Fab
    • Protein or peptide: Spike protein S2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water
KeywordsS2prime / coronavirus / SARS-CoV-2 / spike / fusion / entry / antiviral / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / VIRAL PROTEIN-HYDROLASE complex / C77G12 / VIRAL PROTEIN
Function / homology
Function and homology information


SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMO is proteolytically processed / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / septin ring / SUMOylation of DNA damage response and repair proteins / Transcriptional and post-translational regulation of MITF-M expression and activity ...SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMO is proteolytically processed / SUMOylation of transcription factors / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / septin ring / SUMOylation of DNA damage response and repair proteins / Transcriptional and post-translational regulation of MITF-M expression and activity / SUMOylation of DNA replication proteins / SUMOylation of SUMOylation proteins / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / SUMOylation of RNA binding proteins / SUMOylation of chromatin organization proteins / ubiquitin-like protein ligase binding / protein sumoylation / condensed nuclear chromosome / protein tag activity / symbiont-mediated disruption of host tissue / Maturation of spike protein / Translation of Structural Proteins / Virion Assembly and Release / host cell surface / host extracellular region / symbiont-mediated-mediated suppression of host tetherin activity / Induction of Cell-Cell Fusion / structural constituent of virion / positive regulation of viral entry into host cell / membrane fusion / host cell endoplasmic reticulum-Golgi intermediate compartment membrane / Attachment and Entry / entry receptor-mediated virion attachment to host cell / receptor-mediated virion attachment to host cell / host cell surface receptor binding / symbiont-mediated suppression of host innate immune response / endocytosis involved in viral entry into host cell / receptor ligand activity / fusion of virus membrane with host plasma membrane / fusion of virus membrane with host endosome membrane / viral envelope / symbiont entry into host cell / virion attachment to host cell / host cell plasma membrane / SARS-CoV-2 activates/modulates innate and adaptive immune responses / virion membrane / membrane / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / 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, N-terminal domain superfamily ...Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / 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, N-terminal domain superfamily / Spike S1 subunit, receptor binding domain superfamily, betacoronavirus / Spike glycoprotein, betacoronavirus / Betacoronavirus spike (S) glycoprotein S1 subunit N-terminal (NTD) domain profile. / Spike glycoprotein S1, N-terminal domain, betacoronavirus-like / Betacoronavirus-like spike glycoprotein S1, N-terminal / Betacoronavirus spike (S) glycoprotein S1 subunit C-terminal (CTD) domain profile. / Spike (S) protein S1 subunit, receptor-binding domain, betacoronavirus / Betacoronavirus spike glycoprotein S1, receptor binding / Spike glycoprotein S2 superfamily, coronavirus / 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, coronavirus / Coronavirus spike glycoprotein S2 / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Spike glycoprotein / Small ubiquitin-related modifier
Similarity search - Component
Biological speciesHomo sapiens (human) / Severe acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsMcCallum M / Seattle Structural Genomics Center for Infectious Disease (SSGCID) / Veesler D
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Struct Mol Biol / Year: 2026
Title: TMPRSS2-mediated coronavirus spike activation and inhibition.
Authors: Matthew McCallum / James Brett Case / Jack T Brown / Young-Jun Park / Jimin Lee / Emmajay Sutherland / Anupriya Aggarwal / Cecily Gibson / Florian A Lempp / Cameron Stewart / M Alejandra ...Authors: Matthew McCallum / James Brett Case / Jack T Brown / Young-Jun Park / Jimin Lee / Emmajay Sutherland / Anupriya Aggarwal / Cecily Gibson / Florian A Lempp / Cameron Stewart / M Alejandra Tortorici / Shilpa Sanapala / Jun Siong Low / Daniel Asarnow / Dana Bohan / Exequiel Dellota / Benjamin Merz / Bhavna Chawla / Swagata Kar / Antonio Lanzavecchia / Federica Sallusto / Nicholas M Riley / Stuart Turville / Lisa Purcell / Michael S Diamond / David Veesler /
Abstract: The protease TMPRSS2 facilitates coronavirus infections, yet its mechanism of viral glycoprotein recognition remains unclear. Here we show that, following ACE2 engagement of the SARS-CoV-2 spike (S) ...The protease TMPRSS2 facilitates coronavirus infections, yet its mechanism of viral glycoprotein recognition remains unclear. Here we show that, following ACE2 engagement of the SARS-CoV-2 spike (S) inducing the early fusion intermediate conformation (E-FIC), TMPRSS2 cleaves the R815 S' site and promotes fusogenic conformational changes leading to viral entry. We unveil TMPRSS2 recognition of S', identify key residues modulating binding specificity and demonstrate that S' site-directed broadly neutralizing antibodies target E-FIC and inhibit viral entry by blocking TMPRSS2 access. We computationally designed stabilized E-FIC as a vaccine candidate, overcoming the transient nature of this state. We describe a TMPRSS2-directed monoclonal antibody inhibiting several coronaviruses, including SARS-CoV-2 variants and protecting mice against SARS-CoV-2 challenge. These results outline the mechanistic role of TMPRSS2 and S' site-directed antibodies in coronavirus entry.
History
DepositionFeb 24, 2026-
Header (metadata) releaseMar 18, 2026-
Map releaseMar 18, 2026-
UpdateMay 13, 2026-
Current statusMay 13, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75697.png

Downloads & links

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Map

FileDownload / File: emd_75697.map.gz / Format: CCP4 / Size: 1000 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.)
0.83 Å/pix.
x 640 pix.
= 530.56 Å		0.83 Å/pix.
x 640 pix.
= 530.56 Å		0.83 Å/pix.
x 640 pix.
= 530.56 Å

Surface

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.829 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0
Minimum - Maximum-3.5362113 - 5.851327
Average (Standard dev.)-0.00046110904 (±0.06292573)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions640640640
Spacing640640640
CellA=B=C: 530.56 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_75697_additional_1.map
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Half map: #1

Fileemd_75697_half_map_1.map
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Half map: #2

Fileemd_75697_half_map_2.map
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Sample components

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Entire : SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate ...

EntireName: SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate conformation by circular permutation and clamping by modified EIAV gp45m plus C77G12 Fab
Components
  • Complex: SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate conformation by circular permutation and clamping by modified EIAV gp45m plus C77G12 Fab
    • Protein or peptide: Spike protein S2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water

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Supramolecule #1: SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate ...

SupramoleculeName: SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate conformation by circular permutation and clamping by modified EIAV gp45m plus C77G12 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Spike protein S2

MacromoleculeName: Spike protein S2 / type: protein_or_peptide / ID: 1
Details: Chimeric/circularly permuted construct E-FICS-v3 encodes an azurocidin signal peptide, a serine residue, a SUMO tag (UniProt: Q12306 1-94), an enterokinase cleavage site, a TGTGS linker, ...Details: Chimeric/circularly permuted construct E-FICS-v3 encodes an azurocidin signal peptide, a serine residue, a SUMO tag (UniProt: Q12306 1-94), an enterokinase cleavage site, a TGTGS linker, redesigned equine infectious anemia virus gp45 HR1 (QSNAESVQNHTFEVLNNTIRALELILRKLEILYEMILQLHE), a designed EVEAIQKAI linker, SARS-CoV-2 S residues 914-1131 (with the D985A substitution), a threonine residue, SARS-CoV-2 S residues 703-833, a designed linker (TIDKEK), redesigned equine infectious anemia virus gp45 HR2 (WKEWRKEMENLTKEIKETLEEARKTLKQAEETFKTPSSG), a GT linker, a second enterokinase cleavage site, a modified AVI tag (TGSLNDIFEAQKIEWHE), a QGS linker, and a C-terminal octahistidine tag.
Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Molecular weightTheoretical: 67.78718 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTRLTVLALL AGLLASSRAS MSDSEVNQEA KPEVKPEVKP ETHINLKVSD GSSEIFFKIK KTTPLRRLME AFAKRQGKEM DSLRFLYDG IRIQADQTPE DLDMEDNDII EAHRENDDDD KTGTGSQSNA ESVQNHTFEV LNNTIRALEL ILRKLEILYE M ILQLHEEV ...String:
MTRLTVLALL AGLLASSRAS MSDSEVNQEA KPEVKPEVKP ETHINLKVSD GSSEIFFKIK KTTPLRRLME AFAKRQGKEM DSLRFLYDG IRIQADQTPE DLDMEDNDII EAHRENDDDD KTGTGSQSNA ESVQNHTFEV LNNTIRALEL ILRKLEILYE M ILQLHEEV EAIQKAINVL YENQKLIANQ FNSAIGKIQD SLSSTASALG KLQDVVNQNA QALNTLVKQL SSNFGAISSV LN DILSRLA KVEAEVQIDR LITGRLQSLQ TYVTQQLIRA AEIRASANLA ATKMSECVLG QSKRVDFCGK GYHLMSFPQS APH GVVFLH VTYVPAQEKN FTTAPAICHD GKAHFPREGV FVSNGTHWFV TQRNFYEPQI ITTDNTFVSG NCDVVIGTNS VAYS NNSIA IPTNFTISVT TEILPVSMTK TSVDCTMYIC GDSTECSNLL LQYGSFCTQL NRALTGIAVE QDKNTQEVFA QVKQI YKTP PIKDFGGFNF SQILPDPSKP SKRSFIEDLL FNKVTLADAG FTIDKEKWKE WRKEMENLTK EIKETLEEAR KTLKQA EET FKTPSSGGTD DDDKTGSLND IFEAQKIEWH EQGSHHHHHH HH

UniProtKB: Small ubiquitin-related modifier, Spike glycoprotein, Spike glycoprotein

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

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 12 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #3: water

MacromoleculeName: water / type: ligand / ID: 3 / Number of copies: 63 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / 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 / Nominal defocus max: 2.7 µm / Nominal defocus min: 0.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 225859
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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