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- EMDB-75721: SARS-CoV-2 spike S2 trimer stabilized in the early fusion interme... -

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Basic information

Entry
Database: EMDB / ID: EMD-75721
TitleSARS-CoV-2 spike S2 trimer stabilized in the early fusion intermediate conformation (E-FICs-v3) bound to the VN01H1 Fab
Map datasharpened map
Sample
  • Complex: SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate conformation by circular permutation and clamping by gp45m (E-FICs-v3) bound to the VN01H1 Fab
    • Protein or peptide: SARS-CoV-2 spike S2 trimer stabilized in the early fusion intermediate conformation bound to the VN01H1 Fab
    • Protein or peptide: Light chain of VN01H1 Fab
    • Protein or peptide: Heavy chain of VN01H1 Fab
KeywordsS2prime / coronavirus / SARS-CoV-2 / spike / fusion / entry / antiviral / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / VIRAL PROTEIN-HYDROLASE complex / VN01H1 / VIRAL PROTEIN
Biological speciesHomo sapiens (human) / Severe acute respiratory syndrome coronavirus 2
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 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 25, 2026-
Header (metadata) releaseMay 13, 2026-
Map releaseMay 13, 2026-
UpdateMay 27, 2026-
Current statusMay 27, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_75721.png

Downloads & links

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Map

FileDownload / File: emd_75721.map.gz / Format: CCP4 / Size: 1000 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
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Others
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

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.829 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-3.8692174 - 6.007152
Average (Standard dev.)-0.00034346367 (±0.054112706)
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: unsharpened map

Fileemd_75721_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

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Half map: half map A

Fileemd_75721_half_map_1.map
Annotationhalf map A
Projections & Slices
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Histogram (log scale)

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Half map: half map B

Fileemd_75721_half_map_2.map
Annotationhalf map B
Projections & Slices
AxesZYX

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Slices (1/2)
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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 gp45m (E-FICs-v3) bound to the VN01H1 Fab
Components
  • Complex: SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate conformation by circular permutation and clamping by gp45m (E-FICs-v3) bound to the VN01H1 Fab
    • Protein or peptide: SARS-CoV-2 spike S2 trimer stabilized in the early fusion intermediate conformation bound to the VN01H1 Fab
    • Protein or peptide: Light chain of VN01H1 Fab
    • Protein or peptide: Heavy chain of VN01H1 Fab

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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 gp45m (E-FICs-v3) bound to the VN01H1 Fab
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: SARS-CoV-2 spike S2 trimer stabilized in the early fusion interme...

MacromoleculeName: SARS-CoV-2 spike S2 trimer stabilized in the early fusion intermediate conformation bound to the VN01H1 Fab
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.
Enantiomer: LEVO
Source (natural)Organism: Severe acute respiratory syndrome coronavirus 2
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTRLTVLALL AGLLASSRAS MSDSEVNQEA KPEVKPEVKP ETHINLKVSD GSSEIFFKIK KTTPLRRLME AFAKRQGKEM DSLRFLYDGI RIQADQTPED LDMEDNDIIE AHRENDDDDK TGTGSQSNAE SVQNHTFEVL NNTIRALELI LRKLEILYEM ILQLHEEVEA ...String:
MTRLTVLALL AGLLASSRAS MSDSEVNQEA KPEVKPEVKP ETHINLKVSD GSSEIFFKIK KTTPLRRLME AFAKRQGKEM DSLRFLYDGI RIQADQTPED LDMEDNDIIE AHRENDDDDK TGTGSQSNAE SVQNHTFEVL NNTIRALELI LRKLEILYEM ILQLHEEVEA IQKAINVLYE NQKLIANQFN SAIGKIQDSL SSTASALGKL QDVVNQNAQA LNTLVKQLSS NFGAISSVLN DILSRLAKVE AEVQIDRLIT GRLQSLQTYV TQQLIRAAEI RASANLAATK MSECVLGQSK RVDFCGKGYH LMSFPQSAPH GVVFLHVTYV PAQEKNFTTA PAICHDGKAH FPREGVFVSN GTHWFVTQRN FYEPQIITTD NTFVSGNCDV VIGTNSVAYS NNSIAIPTNF TISVTTEILP VSMTKTSVDC TMYICGDSTE CSNLLLQYGS FCTQLNRALT GIAVEQDKNT QEVFAQVKQI YKTPPIKDFG GFNFSQILPD PSKPSKRSFI EDLLFNKVTL ADAGFTIDKE KWKEWRKEME NLTKEIKETL EEARKTLKQA EETFKTPSSG GTDDDDKTGS LNDIFEAQKI EWHEQGSHHH HHHHH

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Macromolecule #2: Light chain of VN01H1 Fab

MacromoleculeName: Light chain of VN01H1 Fab / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIVMTQSPAT LSVSPGDRAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYG ASTRAAGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ YDNWPSITFG QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK ...String:
DIVMTQSPAT LSVSPGDRAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYG ASTRAAGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ YDNWPSITFG QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC

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Macromolecule #3: Heavy chain of VN01H1 Fab

MacromoleculeName: Heavy chain of VN01H1 Fab / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGG LVLPGGSLRL SCSASGFTFS DFSMHWVRQS PGKGLEYVSA ITSSGSSTYY PDSVKGRFTI SRDNSKNTLY LQMGSLRVED TAVYWCVKNS DVFRFPHLYF DVWGRGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT ...String:
EVQLVESGGG LVLPGGSLRL SCSASGFTFS DFSMHWVRQS PGKGLEYVSA ITSSGSSTYY PDSVKGRFTI SRDNSKNTLY LQMGSLRVED TAVYWCVKNS DVFRFPHLYF DVWGRGTLVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKR VEPKSC

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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: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 121952
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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