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- EMDB-66420: IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure -

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Basic information

Entry
Database: EMDB / ID: EMD-66420
TitleIL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure
Map data
Sample
  • Complex: IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure
    • Protein or peptide: Interleukin-33 (109-270)
    • Protein or peptide: Tozorakimab-L chain
    • Protein or peptide: Tozorakimab-H chain
    • Protein or peptide: Itepekimab-K chain
    • Protein or peptide: Itepekimab-H chain
KeywordsIL33 / antibody Itepekimab fab / antibody Tozorakimab fab / CYTOKINE/IMMUNE SYSTEM / CYTOKINE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


interleukin-33 receptor binding / negative regulation of macrophage proliferation / positive regulation of cellular defense response / Interleukin-33 signaling / positive regulation of MHC class I biosynthetic process / negative regulation of immunoglobulin production / microglial cell activation involved in immune response / negative regulation of T-helper 1 type immune response / negative regulation of leukocyte migration / negative regulation of inflammatory response to wounding ...interleukin-33 receptor binding / negative regulation of macrophage proliferation / positive regulation of cellular defense response / Interleukin-33 signaling / positive regulation of MHC class I biosynthetic process / negative regulation of immunoglobulin production / microglial cell activation involved in immune response / negative regulation of T-helper 1 type immune response / negative regulation of leukocyte migration / negative regulation of inflammatory response to wounding / antibacterial innate immune response / positive regulation of glycoprotein biosynthetic process / microglial cell proliferation / interleukin-33-mediated signaling pathway / positive regulation of type 2 immune response / positive regulation of interleukin-5 production / positive regulation of interleukin-13 production / positive regulation of MHC class II biosynthetic process / positive regulation of macrophage activation / type 2 immune response / positive regulation of neuroinflammatory response / positive regulation of immunoglobulin production / positive regulation of interleukin-4 production / negative regulation of type II interferon production / macrophage differentiation / transport vesicle / extrinsic apoptotic signaling pathway / positive regulation of chemokine production / cytokine activity / positive regulation of cytokine production / response to wounding / positive regulation of interleukin-6 production / positive regulation of inflammatory response / positive regulation of tumor necrosis factor production / protein import into nucleus / PIP3 activates AKT signaling / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / chromosome / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / gene expression / defense response to virus / Ub-specific processing proteases / positive regulation of gene expression / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / : / extracellular region / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
Interleukin-33 / : / Interleukin 33
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsWang XQ / Wang Y
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2022YFF1203103 China
CitationJournal: MAbs / Year: 2026
Title: Structures of clinical antibodies bound to IL-33 uncover two distinct epitopes underlying differential efficacy.
Authors: Jing Chen / Yue Wang / Xinquan Wang /
Abstract: Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, drives type 2 inflammation through signaling via the ST2 and IL-1RAcP receptors, making it a critical therapeutic target for ...Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, drives type 2 inflammation through signaling via the ST2 and IL-1RAcP receptors, making it a critical therapeutic target for inflammatory diseases such as asthma and chronic obstructive pulmonary disease. Current therapeutic strategies have primarily focused on antibodies that target IL-33 or ST2 to disrupt their specific interaction. However, the structural mechanisms underlying antibody-mediated neutralization of IL-33 remain poorly understood. Here, we report the structures of three antibodies in clinical trial - etokimab, itepekimab, and tozorakimab - complexed with IL-33, determined by X-ray crystallography and cryo-electron microscopy. Structural analysis reveals two distinct neutralizing epitopes on IL-33, termed Epitope 1 at IL-33/ST2 binding Site 1 and Epitope 2 at IL-33/ST2 binding Site 2. Tozorakimab, which targets Epitope 1, completely blocks ST2 engagement by sterically occluding the ST2 D1-D2 domain-binding interface. In contrast, etokimab and itepekimab, which recognize Epitope 2, interfere with IL-33 recognition of the ST2 D3 domain and thereby only partially inhibit ST2 binding. These structural and biochemical findings provide a molecular explanation for the differential efficacy of the three antibodies in inhibiting IL-33 signaling in cellular assays. Collectively, our results provide valuable insights into the molecular determinants of efficacy for existing IL-33 therapeutics and offer a structural framework for the rational design of next-generation IL-33 targeted inhibitors.
History
DepositionSep 29, 2025-
Header (metadata) releaseMar 18, 2026-
Map releaseMar 18, 2026-
UpdateMar 18, 2026-
Current statusMar 18, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_66420.png

Downloads & links

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Map

FileDownload / File: emd_66420.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 320 pix.
= 343.744 Å		1.07 Å/pix.
x 320 pix.
= 343.744 Å		1.07 Å/pix.
x 320 pix.
= 343.744 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0742 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-0.3181779 - 1.4582896
Average (Standard dev.)-0.000561279 (±0.025101777)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 343.74402 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_66420_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_66420_half_map_2.map
Projections & Slices
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Sample components

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Entire : IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure

EntireName: IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure
Components
  • Complex: IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure
    • Protein or peptide: Interleukin-33 (109-270)
    • Protein or peptide: Tozorakimab-L chain
    • Protein or peptide: Tozorakimab-H chain
    • Protein or peptide: Itepekimab-K chain
    • Protein or peptide: Itepekimab-H chain

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Supramolecule #1: IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure

SupramoleculeName: IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #4, #2, #5, #3, #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Itepekimab-H chain

MacromoleculeName: Itepekimab-H chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.336883 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLVESGGN LEQPGGSLRL SCTASGFTFS RSAMNWVRRA PGKGLEWVSG ISGSGGRTYY ADSVKGRFTI SRDNSKNTLY LQMNSLSAE DTAAYYCAKD SYTTSWYGGM DVWGHGTTVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL ...String:
EVQLVESGGN LEQPGGSLRL SCTASGFTFS RSAMNWVRRA PGKGLEWVSG ISGSGGRTYY ADSVKGRFTI SRDNSKNTLY LQMNSLSAE DTAAYYCAKD SYTTSWYGGM DVWGHGTTVT VSSASTKGPS VFPLAPSSKS TSGGTAALGC LVKDYFPEPV T VSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVE

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Macromolecule #2: Tozorakimab-L chain

MacromoleculeName: Tozorakimab-L chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 22.409814 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: SYVLTQPPSV SVSPGQTASI TCSGEGMGDK YAAWYQQKPG QSPVLVIYRD TKRPSGIPER FSGSNSGNTA TLTISGTQAM DEADYYCGV IQDNTGVFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS ...String:
SYVLTQPPSV SVSPGQTASI TCSGEGMGDK YAAWYQQKPG QSPVLVIYRD TKRPSGIPER FSGSNSGNTA TLTISGTQAM DEADYYCGV IQDNTGVFGG GTKLTVLGQP KAAPSVTLFP PSSEELQANK ATLVCLISDF YPGAVTVAWK ADSSPVKAGV E TTTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS

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Macromolecule #3: Itepekimab-K chain

MacromoleculeName: Itepekimab-K chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.282912 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DIQMTQSPSS VSASVGDRVT ITCRASQGIF SWLAWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFAIYYCQ QANSVPITFG QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS ...String:
DIQMTQSPSS VSASVGDRVT ITCRASQGIF SWLAWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFAIYYCQ QANSVPITFG QGTRLEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS Q ESVTEQDS KDSTYSLSST LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC

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Macromolecule #4: Interleukin-33 (109-270)

MacromoleculeName: Interleukin-33 (109-270) / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 17.912027 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
ITGISPITEY LASLSTYNDQ SITFALEDES YEIYVEDLKK DEKKDKVLLS YYESQHPSNE SGDGVDGKML MVTLSPTKDF WLHANNKEH SVELHKCEKP LPDQAFFVLH NMHSNCVSFE CKTDPGVFIG VKDNHLALIK VDSSENLSTE NILFKLSET

UniProtKB: Interleukin-33

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Macromolecule #5: Tozorakimab-H chain

MacromoleculeName: Tozorakimab-H chain / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.22424 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSG ISAIDQSTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCARQ KFMQLWGGGL RYPFGYWGQG TMVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF P EPVTVSWN ...String:
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYAMSWVRQA PGKGLEWVSG ISAIDQSTYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAE DTAVYYCARQ KFMQLWGGGL RYPFGYWGQG TMVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF P EPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI CNVNHKPSNT KVDKRVEPK

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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
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: 1.8 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 193399
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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