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- PDB-9k3t: Cryo-EM structure of TMPRSS2 in complex with Fab fragments of 752... -

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Basic information

Entry
Database: PDB / ID: 9k3t
TitleCryo-EM structure of TMPRSS2 in complex with Fab fragments of 752 mAb and 2228 mAb
Components
  • Fab 2228 heavy chain
  • Fab 2228 light chain
  • Fab 752 heavy chain
  • Fab 752 light chain
  • Transmembrane protease serine 2
KeywordsMEMBRANE PROTEIN / HYDROLASE / IMMUNE SYSTEM
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.15 Å
AuthorsKatsura, K. / Hisano, T. / Matsumoto, T. / Shirouzu, M.
Funding support Japan, 1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 15, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Oct 15, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Dec 31, 2025Group: Data collection / Database references / Category: citation / em_admin
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Revision 1.1Dec 31, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transmembrane protease serine 2
L: Fab 752 light chain
H: Fab 752 heavy chain
l: Fab 2228 light chain
h: Fab 2228 heavy chain


Theoretical massNumber of molelcules
Total (without water)140,1585
Polymers140,1585
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Transmembrane protease serine 2 / Serine protease 10


Mass: 43250.609 Da / Num. of mol.: 1 / Mutation: 250SSRQSR255 replaced with DDDDDK
Source method: isolated from a genetically manipulated source
Details: The sequence responsible for TMPRSS2 autoactivation (250SSRQSR255) was substituted with the 6 residues containing an enterokinase cleavage site.
Source: (gene. exp.) Homo sapiens (human) / Gene: TMPRSS2, PRSS10 / Production host: Baculovirus transfer vector pFASTBAC1
References: UniProt: O15393, transmembrane protease serine 2
#2: Antibody Fab 752 light chain


Mass: 23749.342 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#3: Antibody Fab 752 heavy chain


Mass: 24654.529 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#4: Antibody Fab 2228 light chain


Mass: 23919.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
#5: Antibody Fab 2228 heavy chain


Mass: 24584.455 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Homo sapiens (human)
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1TMPRSS2 ECD and Fab fragments complexCOMPLEXall0RECOMBINANT
2TMPRSS2COMPLEX#11RECOMBINANT
3Fab 752COMPLEX#2-#31RECOMBINANT
4Fab 2228COMPLEX#4-#51RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
34Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Baculovirus transfer vector pFASTBAC1136645
23Homo sapiens (human)9606
34Homo sapiens (human)9606
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 20000 nm / Nominal defocus min: 8000 nm
Image recordingElectron dose: 50.1 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.21.2_5419: / Category: model refinement
CTF correctionDetails: CTFFind4 and CTFRefine were used within the RELION3.1.3
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.15 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 80052 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037627
ELECTRON MICROSCOPYf_angle_d0.51910375
ELECTRON MICROSCOPYf_dihedral_angle_d5.0131047
ELECTRON MICROSCOPYf_chiral_restr0.0441126
ELECTRON MICROSCOPYf_plane_restr0.0041326

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