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- PDB-9wwh: Crystal structure of IL-33 and antibody Tozorakimab fab binary complex -

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Basic information

Entry
Database: PDB / ID: 9wwh
TitleCrystal structure of IL-33 and antibody Tozorakimab fab binary complex
Components
  • Interleukin-33 (109-270)
  • Tozorakimab-Heavy chain
  • Tozorakimab-Light chain
KeywordsCYTOKINE/IMMUNE SYSTEM / IL-33 / Antibody / Tozorakimab / 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)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.51 Å
AuthorsWang, X.Q. / Chen, J. / Wang, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Other government2022YFF1203103 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 23, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Mar 18, 2026Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: Tozorakimab-Heavy chain
L: Tozorakimab-Light chain
A: Tozorakimab-Heavy chain
B: Tozorakimab-Light chain
C: Interleukin-33 (109-270)
D: Interleukin-33 (109-270)


Theoretical massNumber of molelcules
Total (without water)127,8636
Polymers127,8636
Non-polymers00
Water00
1
H: Tozorakimab-Heavy chain
L: Tozorakimab-Light chain
D: Interleukin-33 (109-270)


Theoretical massNumber of molelcules
Total (without water)63,9313
Polymers63,9313
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5400 Å2
ΔGint-33 kcal/mol
Surface area25050 Å2
MethodPISA
2
A: Tozorakimab-Heavy chain
B: Tozorakimab-Light chain
C: Interleukin-33 (109-270)


Theoretical massNumber of molelcules
Total (without water)63,9313
Polymers63,9313
Non-polymers00
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5550 Å2
ΔGint-29 kcal/mol
Surface area25380 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13890 Å2
ΔGint-76 kcal/mol
Surface area47490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.442, 162.561, 188.189
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Antibody Tozorakimab-Heavy chain


Mass: 24311.318 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#2: Antibody Tozorakimab-Light chain


Mass: 22322.736 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#3: Protein Interleukin-33 (109-270)


Mass: 17297.338 Da / Num. of mol.: 2
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
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.14 Å3/Da / Density % sol: 60.79 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.2 M Magnesium chloride hexahydrate 0.1 M Na citrate tribasic dihydrate pH 5.0 15% w/v Polyethylene glycol 20,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.97902 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 17, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97902 Å / Relative weight: 1
ReflectionResolution: 3.5→50 Å / Num. obs: 18337 / % possible obs: 87.62 % / Redundancy: 8 % / CC1/2: 0.975 / Net I/σ(I): 17.3
Reflection shellResolution: 3.511→3.637 Å / Num. unique obs: 1535 / CC1/2: 0.476 / % possible all: 76.03

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Processing

Software
NameVersionClassification
PHENIX(1.21_5207: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.51→45.19 Å / SU ML: 0.42 / Cross valid method: NONE / σ(F): 1.34 / Phase error: 25.66 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2593 944 5.15 %
Rwork0.2295 --
obs0.2311 18332 87.61 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.51→45.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8601 0 0 0 8601
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0048821
X-RAY DIFFRACTIONf_angle_d0.77811995
X-RAY DIFFRACTIONf_dihedral_angle_d13.0823173
X-RAY DIFFRACTIONf_chiral_restr0.0461346
X-RAY DIFFRACTIONf_plane_restr0.0061530
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.51-3.690.34181170.33022104X-RAY DIFFRACTION76
3.69-3.930.36931180.32332197X-RAY DIFFRACTION79
3.93-4.230.27641070.26232236X-RAY DIFFRACTION80
4.23-4.650.24351350.22182336X-RAY DIFFRACTION83
4.65-5.330.20921520.19952694X-RAY DIFFRACTION95
5.33-6.710.26961490.22852861X-RAY DIFFRACTION100
6.71-45.190.23991660.19392960X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.3293-0.4519-1.01065.3818-0.42976.76940.00870.6382-0.2773-0.1387-0.83240.9438-0.7612-1.00620.75040.58840.1573-0.23110.8516-0.2740.8494-26.3534.964-46.192
26.089-0.93010.25214.4694-0.37014.2125-0.0732-0.8609-0.44650.8956-0.0615-0.2395-0.20270.0380.15450.9667-0.1754-0.07690.72940.17940.8082-3.708-7.537-18.081
35.0877-1.48451.04277.2715-1.46716.60510.08710.2015-0.0254-0.3745-0.15110.20620.102-0.81870.03230.64580.0361-0.02570.7077-0.04220.4434-23.13-28.346-48.722
47.3011-1.66890.90194.6390.98313.46650.41861.65890.2467-0.4381-0.2108-0.2097-0.2670.4076-0.06140.75940.12550.05731.06410.31431.00393.373-12.486-71.114
53.35230.18021.02981.05950.90214.0140.0831-0.05020.0553-0.1877-0.3664-0.344-0.80640.01050.31051.10780.0103-0.25640.48370.14960.7717-7.72415.774-52.21
62.22970.46971.78294.8193-1.39943.6667-0.07160.71620.64890.5176-0.334-0.3778-0.31550.39660.38680.4911-0.1628-0.18980.69680.20010.92696.311-6.617-31.672
76.2022-2.2977-1.0853.35630.77863.49280.1325-0.0712-0.0894-0.2339-0.3076-0.23010.54180.30710.17710.66650.0039-0.03690.50810.1850.5743-5.415-36.849-38.03
81.5992-1.0969-1.12924.84350.18376.2537-0.9079-0.3248-0.03430.3124-0.11980.32480.06920.90830.81250.48810.12480.00520.85250.38421.20359.349-12.779-55.062
96.0217-0.4232-0.88885.3962-1.73585.0579-0.3441-0.35870.26490.08080.39450.0636-0.288-0.28720.09690.5147-0.0378-0.10820.66310.08070.6181-30.869-37.109-16.159
105.32240.6539-0.89366.42610.12154.497-0.52150.1407-0.1797-0.15210.2104-0.14960.9408-0.03920.27411.02390.0479-0.06150.6953-0.08110.5626-28.21715.021-78.498
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN L AND RESID 3:109 )L3 - 109
2X-RAY DIFFRACTION2( CHAIN L AND RESID 110:209 )L110 - 209
3X-RAY DIFFRACTION3( CHAIN B AND RESID 3:109 )B3 - 109
4X-RAY DIFFRACTION4( CHAIN B AND RESID 110:212 )B110 - 212
5X-RAY DIFFRACTION5( CHAIN H AND RESID 1:126 )H1 - 126
6X-RAY DIFFRACTION6( CHAIN H AND RESID 127:225 )H127 - 225
7X-RAY DIFFRACTION7( CHAIN A AND RESID 1:126 )A1 - 126
8X-RAY DIFFRACTION8( CHAIN A AND RESID 127:225 )A127 - 225
9X-RAY DIFFRACTION9( CHAIN C AND RESID 117:268 )C117 - 268
10X-RAY DIFFRACTION10( CHAIN D AND RESID 117:268 )D117 - 268

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