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- EMDB-48419: Beta1-tryptase monomer bound to inhibitory Fabs E82.AS and E104.v2 -

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Basic information

Entry
Database: EMDB / ID: EMD-48419
TitleBeta1-tryptase monomer bound to inhibitory Fabs E82.AS and E104.v2
Map dataBeta1-tryptase monomer bound to inhibitory Fabs E82.AS and E104.v2
Sample
  • Complex: Human beta1-tryptase bound to inhibitory Fabs E82.AS and E104.v2
    • Protein or peptide: Light chain of E104.v2 Fab
    • Protein or peptide: Tryptase alpha/beta-1
    • Protein or peptide: Heavy chain of E104v2 Fab
    • Protein or peptide: Light chain of E82.AS Fab
    • Protein or peptide: Heavy chain of E82.AS Fab
    • Protein or peptide: Anti-human kappa light chain VHH
KeywordsSerine Protease / Inhibitory Antibodies / IMMUNE SYSTEM / IMMUNE SYSTEM-Hydrolase complex
Function / homology
Function and homology information


tryptase / Activation of Matrix Metalloproteinases / extracellular matrix disassembly / serine-type peptidase activity / defense response / serine-type endopeptidase activity / proteolysis / : / extracellular region / identical protein binding
Similarity search - Function
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
Tryptase alpha/beta-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsAzumaya CM / Maun HR / Rohou AL
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Commun / Year: 2026
Title: Complete inhibition of β-tryptase by tetramer dissociation and active site allostery due to a single antibody residue.
Authors: Henry R Maun / Caleigh M Azumaya / Benjamin T Walters / Rajesh Vij / Ashley Morando / Kelly M Loyet / James T Koerber / Alexis Rohou / Robert A Lazarus /
Abstract: Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of inflammatory responses in asthma, allergy and other diseases. Here we report an anti-β-tryptase antibody ...Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of inflammatory responses in asthma, allergy and other diseases. Here we report an anti-β-tryptase antibody with a superior mechanism of action compared to others since it not only inhibits tetrameric β-tryptase, but also completely inhibits monomeric β-tryptase activity. The antibody binds to an exosite that causes tetramer dissociation as either an IgG or Fab and, in addition, allosterically alters the substrate binding cleft on monomers, thus preventing substrate binding and proteolysis. We solve the cryoEM structure of the complex, generate biochemical data and engineer point mutations to elucidate the allosteric path of inhibition. This ultimately reveals a single Asp to Gly mutation in CDR-L3 that only slightly impacts binding affinity, but completely eliminates inhibitory activity. Finally, we improve antibody inhibitory potency up to 4.7-fold by structure-based design creating new charge-charge interactions. This antibody may have enhanced efficacy and potential to assess the relevance of β-tryptase, including monomers, in biological and clinical settings.
History
DepositionDec 20, 2024-
Header (metadata) releaseApr 22, 2026-
Map releaseApr 22, 2026-
UpdateApr 22, 2026-
Current statusApr 22, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48419.png

Downloads & links

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Map

FileDownload / File: emd_48419.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationBeta1-tryptase monomer bound to inhibitory Fabs E82.AS and E104.v2
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 450 pix.
= 377.1 Å		0.84 Å/pix.
x 450 pix.
= 377.1 Å		0.84 Å/pix.
x 450 pix.
= 377.1 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.838 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.11153819 - 0.2323821
Average (Standard dev.)-0.00005376735 (±0.0032629934)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 377.1 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_48419_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 1

Fileemd_48419_half_map_1.map
Annotationhalf map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map 2

Fileemd_48419_half_map_2.map
Annotationhalf map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human beta1-tryptase bound to inhibitory Fabs E82.AS and E104.v2

EntireName: Human beta1-tryptase bound to inhibitory Fabs E82.AS and E104.v2
Components
  • Complex: Human beta1-tryptase bound to inhibitory Fabs E82.AS and E104.v2
    • Protein or peptide: Light chain of E104.v2 Fab
    • Protein or peptide: Tryptase alpha/beta-1
    • Protein or peptide: Heavy chain of E104v2 Fab
    • Protein or peptide: Light chain of E82.AS Fab
    • Protein or peptide: Heavy chain of E82.AS Fab
    • Protein or peptide: Anti-human kappa light chain VHH

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Supramolecule #1: Human beta1-tryptase bound to inhibitory Fabs E82.AS and E104.v2

SupramoleculeName: Human beta1-tryptase bound to inhibitory Fabs E82.AS and E104.v2
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Light chain of E104.v2 Fab

MacromoleculeName: Light chain of E104.v2 Fab / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.498014 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCQSIKSVY NNRLGWYQQK PGKAPKLLIY ETSILTSGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYC AGGFDRSGDT TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE ...String:
DIQMTQSPSS LSASVGDRVT ITCQSIKSVY NNRLGWYQQK PGKAPKLLIY ETSILTSGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYC AGGFDRSGDT TFGQGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV QWKVDNALQS G NSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGE

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Macromolecule #2: Tryptase alpha/beta-1

MacromoleculeName: Tryptase alpha/beta-1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: tryptase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.476348 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: IVGGQEAPRS KWPWQVSLRV HGPYWMHFCG GSLIHPQWVL TAAHCVGPDV KDLAALRVQL REQHLYYQDQ LLPVSRIIVH PQFYTAQIG ADIALLELEE PVNVSSHVHT VTLPPASETF PPGMPCWVTG WGDVDNDERL PPPFPLKQVK VPIMENHICD A KYHLGAYT ...String:
IVGGQEAPRS KWPWQVSLRV HGPYWMHFCG GSLIHPQWVL TAAHCVGPDV KDLAALRVQL REQHLYYQDQ LLPVSRIIVH PQFYTAQIG ADIALLELEE PVNVSSHVHT VTLPPASETF PPGMPCWVTG WGDVDNDERL PPPFPLKQVK VPIMENHICD A KYHLGAYT GDDVRIVRDD MLCAGNTRRD SCQGDSGGPL VCKVNGTWLQ AGVVSWGEGC AQPNRPGIYT RVTYYLDWIH HY VPKKP

UniProtKB: Tryptase alpha/beta-1

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Macromolecule #3: Heavy chain of E104v2 Fab

MacromoleculeName: Heavy chain of E104v2 Fab / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.209186 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VQLVESGPGL VKPSETLSLT CTVSRFSLIG YAITWIRQPP GKGLEWIGGI SSAATTFYSS WAKSRVTISR DTSKNQVSLK LSSVTAADT AVYYCARDPR GYGAALDRLD LWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT ...String:
VQLVESGPGL VKPSETLSLT CTVSRFSLIG YAITWIRQPP GKGLEWIGGI SSAATTFYSS WAKSRVTISR DTSKNQVSLK LSSVTAADT AVYYCARDPR GYGAALDRLD LWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT V SWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TQTYICNVNH KPSNTKVDKK VEP

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Macromolecule #4: Light chain of E82.AS Fab

MacromoleculeName: Light chain of E82.AS Fab / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.648217 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIVMTQTPAS VSEPVGGTVT IKCQASQSIV SNYLNWYQQK PGQPPKLLIY QASKLASGVP SRFKGSGSGT EYTLTISDLE AADAATYYC QSTDDSSVTA IYDITFGGGT KVEIKRTVAA PSVFIFPPSD EQLKSGTASV VCLLNNFYPR EAKVQWKVDN A LQSGNSQE ...String:
DIVMTQTPAS VSEPVGGTVT IKCQASQSIV SNYLNWYQQK PGQPPKLLIY QASKLASGVP SRFKGSGSGT EYTLTISDLE AADAATYYC QSTDDSSVTA IYDITFGGGT KVEIKRTVAA PSVFIFPPSD EQLKSGTASV VCLLNNFYPR EAKVQWKVDN A LQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHAGL SSPVTKSFNG EC

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Macromolecule #5: Heavy chain of E82.AS Fab

MacromoleculeName: Heavy chain of E82.AS Fab / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.934625 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SVEESRGGLI KPTDTLTLTC TVSGFSLSSY DMNWVRQAPG KELEWIGYIS YGGSTNYASW AKRRATITRN TNENTVTLKV TSLTAADTA TYFCARFDYP TATLDIWGPG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS G ALTSGVHT ...String:
SVEESRGGLI KPTDTLTLTC TVSGFSLSSY DMNWVRQAPG KELEWIGYIS YGGSTNYASW AKRRATITRN TNENTVTLKV TSLTAADTA TYFCARFDYP TATLDIWGPG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS G ALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKKVEP

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Macromolecule #6: Anti-human kappa light chain VHH

MacromoleculeName: Anti-human kappa light chain VHH / type: protein_or_peptide / ID: 6
Details: Actual sequence: HHHHHHGENLYFQGQVQLQESGGGLVQPGGSLRLSCAASGRTISRYAMSWFRQAPGKEREFVAVARRSGDGAFYADSVQGRFTVSRDDAKNTVYLQMNSLKPEDTAVYYCAIDSDTFYSGSYDYWGQGTQVTVSS
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 10.230603 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) ...String:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)

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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

Concentration0.25 mg/mL
BufferpH: 7.5 / Details: 20mM HEPES, 100mM NaCl
GridModel: UltrAuFoil R0./1 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 64.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 26.0 µm / Nominal defocus min: 8.0 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 672348
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
ChainPDB ID
chain_id: E, source_name: AlphaFold, initial_model_type: in silico model
chain_id: F, source_name: AlphaFold, initial_model_type: in silico model
chain_id: K, source_name: PDB, initial_model_type: experimental model

6ana

chain_id: H, source_name: PDB, initial_model_type: experimental model

6vvu

chain_id: L, source_name: PDB, initial_model_type: experimental model

6vvu

chain_id: A, source_name: PDB, initial_model_type: experimental model

6vvu

Output model

PDB-9mnb:
Beta1-tryptase monomer bound to inhibitory Fabs E82.AS and E104.v2

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