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- EMDB-70722: TMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light c... -

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Basic information

Entry
Database: EMDB / ID: EMD-70722
TitleTMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light chain nanobody
Map datasharpened map
Sample
  • Complex: TMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light chain nanobody
    • Protein or peptide: Transmembrane protease serine 2
    • Protein or peptide: H1H7 antibody heavy chain
    • Protein or peptide: H1H7 antibody light chain
    • Protein or peptide: anti-kappa light chain nanobody
  • Ligand: water
KeywordsH1H7 / nanobody / antibody / TMPRSS2 / NL63 / HKU1 / RBD / S2prime / coronavirus / cleavage / SARS-CoV-2 / spike / fusion / protease / entry / antiviral / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / HYDROLASE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


transmembrane protease serine 2 / 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 ...transmembrane protease serine 2 / 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 / protein autoprocessing / ubiquitin-like protein ligase binding / protein sumoylation / Attachment and Entry / serine-type peptidase activity / condensed nuclear chromosome / protein tag activity / Induction of Cell-Cell Fusion / positive regulation of viral entry into host cell / Attachment and Entry / entry receptor-mediated virion attachment to host cell / serine-type endopeptidase activity / proteolysis / extracellular exosome / extracellular region / nucleoplasm / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Scavenger receptor cysteine-rich domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. ...Scavenger receptor cysteine-rich domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / Rad60/SUMO-like domain / Ubiquitin-2 like Rad60 SUMO-like / 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 / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Transmembrane protease serine 2 / Small ubiquitin-related modifier
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 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_70722.png

Downloads & links

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Map

FileDownload / File: emd_70722.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 512 pix.
= 431.616 Å		0.84 Å/pix.
x 512 pix.
= 431.616 Å		0.84 Å/pix.
x 512 pix.
= 431.616 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.843 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-2.7949371 - 4.646806
Average (Standard dev.)-0.00064916734 (±0.050008256)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 431.616 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: unsharpened map

Fileemd_70722_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

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Half map: half map B

Fileemd_70722_half_map_1.map
Annotationhalf map B
Projections & Slices
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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_70722_half_map_2.map
Annotationhalf map A
Projections & Slices
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Sample components

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Entire : TMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light c...

EntireName: TMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light chain nanobody
Components
  • Complex: TMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light chain nanobody
    • Protein or peptide: Transmembrane protease serine 2
    • Protein or peptide: H1H7 antibody heavy chain
    • Protein or peptide: H1H7 antibody light chain
    • Protein or peptide: anti-kappa light chain nanobody
  • Ligand: water

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Supramolecule #1: TMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light c...

SupramoleculeName: TMPRSS2 S441A in complex with the H1H7 Fab and anti-kappa light chain nanobody
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transmembrane protease serine 2

MacromoleculeName: Transmembrane protease serine 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: transmembrane protease serine 2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.429633 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 DGSGLNDIFE AQKIEWHEQS GHHHHHHHH

UniProtKB: Small ubiquitin-related modifier, Transmembrane protease serine 2

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Macromolecule #2: H1H7 antibody heavy chain

MacromoleculeName: H1H7 antibody heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.720721 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQS PGKGLEWVAV IWNDGSYVYY ADSVKGRFTI SRDISKNTLF LQMNSLRAE DTAVYYCARE GEWVLYYFDY WGQGTLVTVS SAATKGPSVF PLAPA(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) ...String:
QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQS PGKGLEWVAV IWNDGSYVYY ADSVKGRFTI SRDISKNTLF LQMNSLRAE DTAVYYCARE GEWVLYYFDY WGQGTLVTVS SAATKGPSVF PLAPA(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)TAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSN TKVDKR VEP

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Macromolecule #3: H1H7 antibody light chain

MacromoleculeName: H1H7 antibody light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.291832 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: IQMTQSPSTL SASVGDRVTI TCRASQSISS WLAWYQQKPG KAPKLLIYKA STLESGVPSR FSGSGSGTEF TLTISSLQPD DFATYYCQQ YNSYSYTFGQ GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK ...String:
IQMTQSPSTL SASVGDRVTI TCRASQSISS WLAWYQQKPG KAPKLLIYKA STLESGVPSR FSGSGSGTEF TLTISSLQPD DFATYYCQQ YNSYSYTFGQ GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ E SVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGE

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Macromolecule #4: anti-kappa light chain nanobody

MacromoleculeName: anti-kappa light chain nanobody / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 17.252107 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MKKTAIAIAV ALAGFATVAQ AAPMGSQVQL QESGGGLVQP GGSLRLSCAA SGRTISRYAM SWFRQAPGKE REFVAVARRS GDGAFYADS VQGRFTVSRD DAKNTVYLQM NSLKPEDTAV YYCAIDSDTF YSGSYDYWGQ GTQVTVSSHH HHHHHHEPEA

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 38 / 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: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 117441
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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