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- PDB-9z3j: HCoV-NL63 S2' peptide bound to TMPRSS2 S441A (complexed with the ... -

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Basic information

Entry
Database: PDB / ID: 9z3j
TitleHCoV-NL63 S2' peptide bound to TMPRSS2 S441A (complexed with the H1H7 Fab and an anti-kappa-nanobody)
Components
  • H1H7 heavy chain
  • H1H7 light chain
  • HCoV-NL63 S2' peptide
  • Inactive TMPRSS2 construct
  • anti-kappa nanobody
KeywordsVIRAL PROTEIN/Immune System / TMPRSS2 / NL63 / S2prime / coronavirus / cleavage / SARS-CoV-2 / spike / fusion / protease / entry / antiviral / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / VIRAL PROTEIN / VIRAL PROTEIN-Immune System 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 / 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 glycoprotein S2, coronavirus, C-terminal / Coronavirus spike glycoprotein S2, intravirion ...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 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 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
Similarity search - Component
Biological speciesHuman coronavirus NL63
Homo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsMcCallum, M. / Seattle Structural Genomics Center for Infectious Disease (SSGCID) / Veesler, D.
Funding support United States, 1items
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
DepositionNov 6, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 13, 2026Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 13, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: HCoV-NL63 S2' peptide
B: Inactive TMPRSS2 construct
H: H1H7 heavy chain
L: H1H7 light chain
N: anti-kappa nanobody
hetero molecules


Theoretical massNumber of molelcules
Total (without water)124,8826
Polymers124,3125
Non-polymers5711
Water1,60389
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Antibody , 3 types, 3 molecules HLN

#3: Antibody H1H7 heavy chain


Mass: 24054.004 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Antibody H1H7 light chain


Mass: 23510.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#5: Antibody anti-kappa nanobody


Mass: 17252.107 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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Protein/peptide / Protein / Sugars / Non-polymers , 4 types, 92 molecules AB

#1: Protein/peptide HCoV-NL63 S2' peptide


Mass: 1678.952 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human coronavirus NL63 / Gene: S, 2 / Production host: Homo sapiens (human) / References: UniProt: Q6Q1S2
#2: Protein Inactive TMPRSS2 construct


Mass: 57816.820 Da / Num. of mol.: 1 / Mutation: S441A
Source method: isolated from a genetically manipulated source
Details: The inactive TMPRSS2 construct comprises an azurocidin signal peptide (MTRLTVLALLAGLLASSRA), a serine residue, a SUMO tag (UniProt Q12306; 1-94, ...Details: The inactive TMPRSS2 construct comprises an azurocidin signal peptide (MTRLTVLALLAGLLASSRA), a serine residue, a SUMO tag (UniProt Q12306; 1-94, MSDSEVNQEAKPEVKPEVKPETHINLKVSDGSSEIFFKIKKTTPLRRLMEAFAKRQGKEMDSLRFLYDGIRIQADQTPEDLDMEDNDIIEAHREN), an enteropeptidase cleavage site (NDDDDK), a TT linker, residues 109-492 of TMPRSS2 (UniProt O15393; numbering without start methionine), a C-terminal enteropeptidase site (DDDDK), an SG linker and an octahistidine tag. TMPRSS2 harbors the following substitutions: an internal enteropeptidase site introduced by substituting R251QSR254 to DDDDK, the S441A substitution to make it catalytically inactive and the T447C stabilizing substitution
Source: (gene. exp.) Homo sapiens (human) / Gene: AZU1, SMT3, YDR510W, D9719.15, TMPRSS2, PRSS10 / Production host: Homo sapiens (human) / References: UniProt: O15393
#6: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 570.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4[LFucpa1-6]DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1221m-1a_1-5]/1-1-2/a4-b1_a6-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}[(6+1)][a-L-Fucp]{}}LINUCSPDB-CARE
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 89 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
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

ComponentName: HCoV-NL63 S2' peptide bound to TMPRSS2 S441A (complexed with the H1H7 Fab and an anti-kappa-nanobody)
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: 2700 nm / Nominal defocus min: 200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 270089 / Symmetry type: POINT
RefinementHighest resolution: 2.8 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0046851
ELECTRON MICROSCOPYf_angle_d0.5969349
ELECTRON MICROSCOPYf_dihedral_angle_d4.675966
ELECTRON MICROSCOPYf_chiral_restr0.0471038
ELECTRON MICROSCOPYf_plane_restr0.0051204

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