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- EMDB-70721: TMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fuse... -

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Entry
Database: EMDB / ID: EMD-70721
TitleTMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fused to the HCoV-HKU1 RBD
Map dataJ892
Sample
  • Complex: TMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fused to the HCoV-HKU1 RBD
    • Protein or peptide: NL63-S2prime/HKU1-RBD
    • Protein or peptide: Transmembrane protease serine 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsTMPRSS2 / NL63 / HKU1 / RBD / S2prime / coronavirus / cleavage / SARS-CoV-2 / spike / fusion / protease / entry / antiviral / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / VIRAL PROTEIN-HYDROLASE complex
Function / homology
Function and homology information


transmembrane protease serine 2 / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / Induction of Cell-Cell Fusion / positive regulation of viral entry into host cell / 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 ...transmembrane protease serine 2 / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / Induction of Cell-Cell Fusion / positive regulation of viral entry into host cell / 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 / endocytosis involved in viral entry into host cell / fusion of virus membrane with host plasma membrane / serine-type endopeptidase activity / fusion of virus membrane with host endosome membrane / viral envelope / host cell plasma membrane / virion membrane / proteolysis / extracellular exosome / extracellular region / nucleoplasm / membrane / plasma membrane
Similarity search - Function
Spike glycoprotein, Alphacoronavirus / Scavenger receptor cysteine-rich domain / Spike glycoprotein S1, coronavirus / Coronavirus spike glycoprotein S1 / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / Spike (S) protein S1 subunit, N-terminal domain, murine hepatitis virus-like / Spike glycoprotein S2, coronavirus, C-terminal ...Spike glycoprotein, Alphacoronavirus / Scavenger receptor cysteine-rich domain / Spike glycoprotein S1, coronavirus / Coronavirus spike glycoprotein S1 / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / Spike (S) protein S1 subunit, N-terminal domain, murine hepatitis virus-like / Spike glycoprotein S2, coronavirus, C-terminal / Coronavirus spike glycoprotein S2, intravirion / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / 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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Transmembrane protease serine 2 / Spike glycoprotein / Spike glycoprotein
Similarity search - Component
Biological speciesHomo sapiens (human) / Human coronavirus HKU1
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 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
DepositionMay 19, 2025-
Header (metadata) releaseMay 13, 2026-
Map releaseMay 13, 2026-
UpdateMay 13, 2026-
Current statusMay 13, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70721.png

Downloads & links

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Map

FileDownload / File: emd_70721.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationJ892
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 440 pix.
= 364.76 Å		0.83 Å/pix.
x 440 pix.
= 364.76 Å		0.83 Å/pix.
x 440 pix.
= 364.76 Å

Surface

Projections

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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: 0.65
Minimum - Maximum-3.506489 - 4.9957757
Average (Standard dev.)0.000521433 (±0.04895962)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 364.76 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: J892

Fileemd_70721_additional_1.map
AnnotationJ892
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: J892

Fileemd_70721_half_map_1.map
AnnotationJ892
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: J892

Fileemd_70721_half_map_2.map
AnnotationJ892
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : TMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fuse...

EntireName: TMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fused to the HCoV-HKU1 RBD
Components
  • Complex: TMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fused to the HCoV-HKU1 RBD
    • Protein or peptide: NL63-S2prime/HKU1-RBD
    • Protein or peptide: Transmembrane protease serine 2
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: TMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fuse...

SupramoleculeName: TMPRSS2 (S441A) bound to the HCoV-NL63 S2'region genetically fused to the HCoV-HKU1 RBD
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NL63-S2prime/HKU1-RBD

MacromoleculeName: NL63-S2prime/HKU1-RBD / type: protein_or_peptide / ID: 1
Details: The NL63-S2'/HKU1-RBD construct comprises a signal peptide (MGILPSPGMPALLSLVSLLSVLLMGCVAETGT), HKU1 (Uniprot: Q5MQD0, isolate N1) residues 320-509, HCoV-NL63 residues I867-L877 (IAGRSALEDLL, ...Details: The NL63-S2'/HKU1-RBD construct comprises a signal peptide (MGILPSPGMPALLSLVSLLSVLLMGCVAETGT), HKU1 (Uniprot: Q5MQD0, isolate N1) residues 320-509, HCoV-NL63 residues I867-L877 (IAGRSALEDLL, Uniprot: Q6Q1S2), a GSGSGSP linker and HKU1 (Uniprot: Q5MQD0, isolate N1) residues 511-614, a GSSGGS linker, an avi-tag (GLNDIFEAQKIEWHE), a GGS linker and an octa-histidine tag
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human coronavirus HKU1
Molecular weightTheoretical: 41.123793 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGILPSPGMP ALLSLVSLLS VLLMGCVAET GTRIPDLPDC DIDKWLNNFN VPSPLNWERK IFSNCNFNLS TLLRLVHTDS FSCNNFDES KIYGSCFKSI VLDKFAIPNS RRSDLQLGSS GFLQSSNYKI DTTSSSCQLY YSLPAINVTI NNYNPSSWNR R YGFNNFNL ...String:
MGILPSPGMP ALLSLVSLLS VLLMGCVAET GTRIPDLPDC DIDKWLNNFN VPSPLNWERK IFSNCNFNLS TLLRLVHTDS FSCNNFDES KIYGSCFKSI VLDKFAIPNS RRSDLQLGSS GFLQSSNYKI DTTSSSCQLY YSLPAINVTI NNYNPSSWNR R YGFNNFNL SSHSVVYSRY CFSVNNTFCP CAKPSFASSC KSHKPPSASC PIGTNYRSCE STTVIAGRSA LEDLLGSGSG SP DHTDWCR CSCLPDPITA YDPRSCSQKK SLVGVGEHCA GFGVDEEKCG VLDGSYNVSC LCSTDAFLGW SYDTCVSNNR CNI FSNFIL NGINSGTTCS NDLLQPNTGS SGGSGLNDIF EAQKIEWHEG GSHHHHHHHH

UniProtKB: Spike glycoprotein, Spike glycoprotein, Spike glycoprotein

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Macromolecule #2: Transmembrane protease serine 2

MacromoleculeName: Transmembrane protease serine 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: transmembrane protease serine 2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.152125 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MTRLTVLALL AGLLASSRAS MSDSEVNQEA KPEVKPEVKP ETHINLKVSD GSSEIFFKIK KTTPLRRLME AFAKRQGKEM DSLRFLYDG IRIQADQTPE DLDMEDNDII EAHRENDDDD KTTGSKCSNS GIECDSSGTC INPSNWCDGV SHCPGGEDEN R CVRLYGPN ...String:
MTRLTVLALL AGLLASSRAS MSDSEVNQEA KPEVKPEVKP ETHINLKVSD GSSEIFFKIK KTTPLRRLME AFAKRQGKEM DSLRFLYDG IRIQADQTPE DLDMEDNDII EAHRENDDDD KTTGSKCSNS GIECDSSGTC INPSNWCDGV SHCPGGEDEN R CVRLYGPN FILQVYSSQR KSWHPVCQDD WNENYGRAAC RDMGYKNNFY SSQGIVDDSG STSFMKLNTS AGNVDIYKKL YH SDACSSK AVVSLRCIAC GVNLNSSDDD DKIVGGESAL PGAWPWQVSL HVQNVHVCGG SIITPEWIVT AAHCVEKPLN NPW HWTAFA GILRQSFMFY GAGYQVEKVI SHPNYDSKTK NNDIALMKLQ KPLTFNDLVK PVCLPNPGMM LQPEQLCWIS GWGA TEEKG KTSEVLNAAK VLLIETQRCN SRYVYDNLIT PAMICAGFLQ GNVDSCQGDA GGPLVCSKNN IWWLIGDTSW GSGCA KAYR PGVYGNVMVF TDWIYRQMRA DG

UniProtKB: Transmembrane protease serine 2

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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: 6 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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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: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 163873
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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