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- EMDB-62028: Cryo-EM structure of TMPRSS2 in complex with Fab fragments of 752... -

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Basic information

Entry
Database: EMDB / ID: EMD-62028
TitleCryo-EM structure of TMPRSS2 in complex with Fab fragments of 752 mAb and 2228 mAb
Map data
Sample
  • Complex: TMPRSS2 ECD and Fab fragments complex
    • Complex: TMPRSS2
      • Protein or peptide: Transmembrane protease serine 2
    • Complex: Fab 752
      • Protein or peptide: Fab 752 light chain
      • Protein or peptide: Fab 752 heavy chain
    • Complex: Fab 2228
      • Protein or peptide: Fab 2228 light chain
      • Protein or peptide: Fab 2228 heavy chain
KeywordsHYDROLASE / IMMUNE SYSTEM / MEMBRANE PROTEIN
Function / homology
Function and homology information


transmembrane protease serine 2 / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / viral translation / Induction of Cell-Cell Fusion / entry receptor-mediated virion attachment to host cell / Attachment and Entry / positive regulation of viral entry into host cell / serine-type endopeptidase activity ...transmembrane protease serine 2 / protein autoprocessing / Attachment and Entry / serine-type peptidase activity / viral translation / Induction of Cell-Cell Fusion / entry receptor-mediated virion attachment to host cell / Attachment and Entry / positive regulation of viral entry into host cell / serine-type endopeptidase activity / proteolysis / extracellular exosome / extracellular region / nucleoplasm / plasma membrane
Similarity search - Function
Scavenger receptor cysteine-rich domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / 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 ...Scavenger receptor cysteine-rich domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / 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 / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Transmembrane protease serine 2
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsKatsura K / Hisano T / Matsumoto T / Shirouzu M
Funding support Japan, 1 items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED) Japan
CitationJournal: iScience / Year: 2025
Title: Monoclonal antibodies against human TMPRSS2 prevent infection by any SARS-CoV-2 variant.
Authors: Michishige Harada / Takehisa Matsumoto / Mizuki Yamamoto / Jin Goda / Akiko Idei / Kenichi Ohtaki / Natsuki Kojima / Natsumi Yoneda / Kosuke Miyauchi / Kazushige Katsura / Mariko Ikeda / ...Authors: Michishige Harada / Takehisa Matsumoto / Mizuki Yamamoto / Jin Goda / Akiko Idei / Kenichi Ohtaki / Natsuki Kojima / Natsumi Yoneda / Kosuke Miyauchi / Kazushige Katsura / Mariko Ikeda / Kazuharu Hanada / Yoshiko Ishizuka-Katsura / Toshiaki Hosaka / Tamao Hisano / Toshie Kaizuka / Takako Yamamoto / Masashi Matsuda / Manabu Nakayama / Akiko Sugimoto-Ishige / Machie Sakuma / Rina Hashimoto / Kazuo Takayama / Misako Nakayama / Cong Thanh Nguyen / Hirohito Ishigaki / Yasushi Itoh / Yoshinobu Hashizume / Minoru Yoshida / Yasushi Kawaguchi / Makoto Takeda / Haruhiko Koseki / Mikako Shirouzu / Jun-Ichiro Inoue / Takashi Saito /
Abstract: The transmembrane serine protease 2 (TMPRSS2) plays a critical role in SARS-CoV-2 infection by priming the viral Spike (S) protein for host cell entry and thus represents a potential target for COVID- ...The transmembrane serine protease 2 (TMPRSS2) plays a critical role in SARS-CoV-2 infection by priming the viral Spike (S) protein for host cell entry and thus represents a potential target for COVID-19 therapy. Here monoclonal antibodies (mAbs) against human TMPRSS2 were established for therapeutic application. infection by SARS-CoV-2 of cell lines and human lung organoids was strongly inhibited by the TMPRSS2 mAbs. These mAbs inhibited infection of all SARS-CoV-2 variants tested including omicron. mAbs recognized epitopes different from the enzymatic active site and did not inhibit protease activity, suggesting blockade of steric interactions of S protein-ACE2/TMPRSS2. The inhibitory activity of the mAbs was examined in human /-double knock-in mouse and macaque models. Analysis of viral titers and histopathological analysis of the lung in these infected animals indicated that the TMPRSS2 mAb effectively suppressed viral titers and induction of inflammation .
History
DepositionOct 20, 2024-
Header (metadata) releaseOct 15, 2025-
Map releaseOct 15, 2025-
UpdateDec 31, 2025-
Current statusDec 31, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_62028.png

Downloads & links

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Map

FileDownload / File: emd_62028.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 300 pix.
= 248.55 Å		0.83 Å/pix.
x 300 pix.
= 248.55 Å		0.83 Å/pix.
x 300 pix.
= 248.55 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8285 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 8.0
Minimum - Maximum-66.0411 - 76.829880000000003
Average (Standard dev.)-0.00000000001033 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 248.54999 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_62028_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_62028_half_map_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_62028_half_map_2.map
Projections & Slices
AxesZYX

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Histogram (log scale)

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Sample components

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Entire : TMPRSS2 ECD and Fab fragments complex

EntireName: TMPRSS2 ECD and Fab fragments complex
Components
  • Complex: TMPRSS2 ECD and Fab fragments complex
    • Complex: TMPRSS2
      • Protein or peptide: Transmembrane protease serine 2
    • Complex: Fab 752
      • Protein or peptide: Fab 752 light chain
      • Protein or peptide: Fab 752 heavy chain
    • Complex: Fab 2228
      • Protein or peptide: Fab 2228 light chain
      • Protein or peptide: Fab 2228 heavy chain

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Supramolecule #1: TMPRSS2 ECD and Fab fragments complex

SupramoleculeName: TMPRSS2 ECD and Fab fragments complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: TMPRSS2

SupramoleculeName: TMPRSS2 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Fab 752

SupramoleculeName: Fab 752 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Mus musculus (house mouse)

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Supramolecule #4: Fab 2228

SupramoleculeName: Fab 2228 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #4-#5
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Transmembrane protease serine 2

MacromoleculeName: Transmembrane protease serine 2 / type: protein_or_peptide / ID: 1
Details: The sequence responsible for TMPRSS2 autoactivation (250SSRQSR255) was substituted with the 6 residues containing an enterokinase cleavage site.
Number of copies: 1 / Enantiomer: LEVO / EC number: transmembrane protease serine 2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.250609 KDa
Recombinant expressionOrganism: Baculovirus transfer vector pFASTBAC1
SequenceString: GMGSKCSNSG IECDSSGTCI NPSNWCDGVS HCPGGEDENR CVRLYGPNFI LQVYSSQRKS WHPVCQDDWN ENYGRAACRD MGYKNNFYS SQGIVDDSGS TSFMKLNTSA GNVDIYKKLY HSDACSSKAV VSLRCIACGV NLNDDDDDKI VGGESALPGA W PWQVSLHV ...String:
GMGSKCSNSG IECDSSGTCI NPSNWCDGVS HCPGGEDENR CVRLYGPNFI LQVYSSQRKS WHPVCQDDWN ENYGRAACRD MGYKNNFYS SQGIVDDSGS TSFMKLNTSA GNVDIYKKLY HSDACSSKAV VSLRCIACGV NLNDDDDDKI VGGESALPGA W PWQVSLHV QNVHVCGGSI ITPEWIVTAA HCVEKPLNNP WHWTAFAGIL RQSFMFYGAG YQVEKVISHP NYDSKTKNND IA LMKLQKP LTFNDLVKPV CLPNPGMMLQ PEQLCWISGW GATEEKGKTS EVLNAAKVLL IETQRCNSRY VYDNLITPAM ICA GFLQGN VDSCQGDSGG PLVTSKNNIW WLIGDTSWGS GCAKAYRPGV YGNVMVFTDW IYRQMRADGE NLYFQ

UniProtKB: Transmembrane protease serine 2

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Macromolecule #2: Fab 752 light chain

MacromoleculeName: Fab 752 light chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.749342 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS LSASLGGKVT ITCKASQDIN KYIAWYQHKP GKGPRLLIHY TSTLQPGIPS RFSGSGSGRD YSFSIYNLEP EDIATYYCL QYYNLWTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK ...String:
DIQMTQSPSS LSASLGGKVT ITCKASQDIN KYIAWYQHKP GKGPRLLIHY TSTLQPGIPS RFSGSGSGRD YSFSIYNLEP EDIATYYCL QYYNLWTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVKWKI DGSERQNGVL N SWTDQDSK DSTYSMSSTL TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC

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Macromolecule #3: Fab 752 heavy chain

MacromoleculeName: Fab 752 heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.654529 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DQVQLQQSGA ELARPGASVK LSCKASGYTF TSCGISWVKQ RTGQGLEWIG EIYPRGGNTY YNEKFKGKAT LTADKSSSTA YMELRSLTS EDSAVYFCAR ENGNYDPLFA YWGQGTLVTV SAAKTTPPSV YPLAPGSAAQ TNSMVTLGCL VKGYFPEPVT V TWNSGSLS ...String:
DQVQLQQSGA ELARPGASVK LSCKASGYTF TSCGISWVKQ RTGQGLEWIG EIYPRGGNTY YNEKFKGKAT LTADKSSSTA YMELRSLTS EDSAVYFCAR ENGNYDPLFA YWGQGTLVTV SAAKTTPPSV YPLAPGSAAQ TNSMVTLGCL VKGYFPEPVT V TWNSGSLS SGVHTFPAVL QSDLYTLSSS VTVPSSTWPS QTVTCNVAHP ASSTKVDKKI VPRDCENLYF Q

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Macromolecule #4: Fab 2228 light chain

MacromoleculeName: Fab 2228 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.919504 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DVVVTQSPAS LAVSLGQRAT ISCRASKSVS TSGYSFMHWY QQKPGQPPKL LIYLASNLES GVPARFSGSG SGTDFILNIH PVEEEDAAT YYCQHSRELP LTFGAGTKLE LKRADAAPTV SIFPPSSEQL TSGGASVVCF LNNFYPKDIN VKWKIDGSER Q NGVLNSWT ...String:
DVVVTQSPAS LAVSLGQRAT ISCRASKSVS TSGYSFMHWY QQKPGQPPKL LIYLASNLES GVPARFSGSG SGTDFILNIH PVEEEDAAT YYCQHSRELP LTFGAGTKLE LKRADAAPTV SIFPPSSEQL TSGGASVVCF LNNFYPKDIN VKWKIDGSER Q NGVLNSWT DQDSKDSTYS MSSTLTLTKD EYERHNSYTC EATHKTSTSP IVKSFNRNEC

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Macromolecule #5: Fab 2228 heavy chain

MacromoleculeName: Fab 2228 heavy chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.584455 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DQVQLQQSGP ELVKPGTSVK ISCKASGYTF TDYYINWVKQ RPGQGLEWIG WIFPGSGSSY YNAIFKGKAT LTVDTSSNTA HMSLSSLTS DDSAVYFCAR GDFGNFGGFF TYWGQGTLVT VSAAKTTAPS VYPLAPVCGG TTGSSVTLGC LVKGYFPEPV T LTWNSGSL ...String:
DQVQLQQSGP ELVKPGTSVK ISCKASGYTF TDYYINWVKQ RPGQGLEWIG WIFPGSGSSY YNAIFKGKAT LTVDTSSNTA HMSLSSLTS DDSAVYFCAR GDFGNFGGFF TYWGQGTLVT VSAAKTTAPS VYPLAPVCGG TTGSSVTLGC LVKGYFPEPV T LTWNSGSL SSGVHTFPAL LQSGLYTLSS SVTVTSNTWP SQTITCNVAH PASSTKVDKK IEPRVPENLY FQ

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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 BIOCONTINUUM (6k x 4k) / Average electron dose: 50.1 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 20.0 µm / Nominal defocus min: 8.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionDetails: CTFFind4 and CTFRefine were used within the RELION3.1.3
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE / Details: Initial model generation in cryoSPARC.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 80052
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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