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- PDB-9x05: IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure -

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Basic information

Entry
Database: PDB / ID: 9x05
TitleIL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure
Components
  • Interleukin-33 (109-270)
  • Itepekimab-H chain
  • Itepekimab-K chain
  • Tozorakimab-H chain
  • Tozorakimab-L chain
KeywordsCYTOKINE/IMMUNE SYSTEM / IL33 / antibody Itepekimab fab / antibody Tozorakimab fab / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsWang, X.Q. / Wang, Y.
Funding support China, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 18, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 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

Downloads & links

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Assembly

Deposited unit
B: Itepekimab-H chain
C: Tozorakimab-L chain
E: Itepekimab-K chain
A: Interleukin-33 (109-270)
D: Tozorakimab-H chain


Theoretical massNumber of molelcules
Total (without water)111,1665
Polymers111,1665
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: Antibody Itepekimab-H chain


Mass: 23336.883 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody Tozorakimab-L chain


Mass: 22409.814 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Antibody Itepekimab-K chain


Mass: 23282.912 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: Protein Interleukin-33 (109-270)


Mass: 17912.027 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL33, C9orf26, IL1F11, NFHEV / Production host: Escherichia coli (E. coli) / References: UniProt: O95760
#5: Antibody Tozorakimab-H chain


Mass: 24224.240 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / 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

ComponentName: IL-33 and Itepekimab fab and Tozorakimab fab ternary complex structure
Type: COMPLEX / Entity ID: #4, #2, #5, #3, #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7
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: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.18.2_3874:model refinement
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 193399 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0057547
ELECTRON MICROSCOPYf_angle_d0.64910274
ELECTRON MICROSCOPYf_dihedral_angle_d6.2171078
ELECTRON MICROSCOPYf_chiral_restr0.0451141
ELECTRON MICROSCOPYf_plane_restr0.0051344

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