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- PDB-3hmx: Crystal structure of ustekinumab FAB/IL-12 complex -

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Basic information

Entry
Database: PDB / ID: 3hmx
TitleCrystal structure of ustekinumab FAB/IL-12 complex
Components
  • (Interleukin-12 subunit ...) x 2
  • (USTEKINUMAB FAB ...) x 2
KeywordsCytokine/IMMUNE SYSTEM / USTEKINUMAB / CNTO1275 / IL-12 / IL-23 / ANTIBODY / FAB / MONOCLONAL ANTIBODY / IMMUNE SYSTEM / Cytokine / Disulfide bond / Glycoprotein / Immunoglobulin domain / Secreted / Growth factor / Cytokine-MMUNE SYSTEM COMPLEX / Cytokine-IMMUNE SYSTEM complex
Function / homology
Function and homology information


interleukin-27 binding / interleukin-12 beta subunit binding / late endosome lumen / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / natural killer cell activation involved in immune response / positive regulation of dendritic cell chemotaxis / positive regulation of natural killer cell activation / positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target ...interleukin-27 binding / interleukin-12 beta subunit binding / late endosome lumen / interleukin-12 alpha subunit binding / interleukin-12 complex / interleukin-23 complex / natural killer cell activation involved in immune response / positive regulation of dendritic cell chemotaxis / positive regulation of natural killer cell activation / positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / negative regulation of vascular endothelial growth factor signaling pathway / negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis / positive regulation of lymphocyte proliferation / positive regulation of tissue remodeling / positive regulation of smooth muscle cell apoptotic process / positive regulation of NK T cell activation / positive regulation of T-helper 1 type immune response / sexual reproduction / positive regulation of natural killer cell mediated cytotoxicity / positive regulation of mononuclear cell proliferation / interleukin-12 receptor binding / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of NK T cell proliferation / T-helper cell differentiation / positive regulation of memory T cell differentiation / Interleukin-12 signaling / Interleukin-35 Signalling / positive regulation of natural killer cell proliferation / positive regulation of osteoclast differentiation / negative regulation of interleukin-17 production / cytokine receptor activity / natural killer cell activation / response to UV-B / positive regulation of granulocyte macrophage colony-stimulating factor production / positive regulation of tyrosine phosphorylation of STAT protein / T-helper 1 type immune response / negative regulation of interleukin-10 production / defense response to protozoan / Interleukin-10 signaling / positive regulation of interleukin-17 production / positive regulation of activated T cell proliferation / positive regulation of interleukin-10 production / cell surface receptor signaling pathway via JAK-STAT / negative regulation of protein secretion / positive regulation of T-helper 17 cell lineage commitment / positive regulation of T cell proliferation / T cell proliferation / extrinsic apoptotic signaling pathway / positive regulation of defense response to virus by host / positive regulation of interleukin-12 production / positive regulation of cell adhesion / regulation of cytokine production / cytokine activity / growth factor activity / negative regulation of smooth muscle cell proliferation / negative regulation of inflammatory response to antigenic stimulus / positive regulation of non-canonical NF-kappaB signal transduction / response to virus / cellular response to virus / positive regulation of T cell mediated cytotoxicity / cellular response to type II interferon / positive regulation of type II interferon production / positive regulation of inflammatory response / positive regulation of tumor necrosis factor production / cell migration / cellular response to lipopolysaccharide / defense response to Gram-negative bacterium / Interleukin-4 and Interleukin-13 signaling / defense response to virus / response to lipopolysaccharide / defense response to Gram-positive bacterium / immune response / endoplasmic reticulum lumen / protein heterodimerization activity / protein-containing complex binding / cell surface / extracellular space / extracellular region / identical protein binding / membrane / cytosol
Similarity search - Function
Interleukin-12 alpha / Interleukin-12 alpha subunit / Interleukin-12 beta / Interleukin-12 beta, central domain / : / Cytokine interleukin-12p40 C-terminus / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core ...Interleukin-12 alpha / Interleukin-12 alpha subunit / Interleukin-12 beta / Interleukin-12 beta, central domain / : / Cytokine interleukin-12p40 C-terminus / Long hematopoietin receptor, soluble alpha chain, conserved site / Long hematopoietin receptor, soluble alpha chains family signature. / Growth Hormone; Chain: A; - #10 / Four-helical cytokine-like, core / Growth Hormone; Chain: A; / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Interleukin-12 subunit alpha / Interleukin-12 subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsLuo, J.
CitationJournal: J.Mol.Biol. / Year: 2010
Title: Structural basis for the dual recognition of IL-12 and IL-23 by ustekinumab.
Authors: Luo, J. / Wu, S.J. / Lacy, E.R. / Orlovsky, Y. / Baker, A. / Teplyakov, A. / Obmolova, G. / Heavner, G.A. / Richter, H.T. / Benson, J.
History
DepositionMay 29, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 9, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jul 22, 2015Group: Database references
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _atom_site_anisotrop.U[1][1] / _atom_site_anisotrop.U[1][2] / _atom_site_anisotrop.U[1][3] / _atom_site_anisotrop.U[2][2] / _atom_site_anisotrop.U[2][3] / _atom_site_anisotrop.U[3][3] / _atom_site_anisotrop.pdbx_auth_asym_id / _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_asym_id / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Nov 27, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Interleukin-12 subunit beta
B: Interleukin-12 subunit alpha
L: USTEKINUMAB FAB LIGHT CHAIN
H: USTEKINUMAB FAB HEAVY CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,0555
Polymers105,1454
Non-polymers9111
Water79344
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.092, 116.435, 182.781
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Antibody , 3 types, 3 molecules ALH

#1: Antibody Interleukin-12 subunit beta / IL-12B / IL-12 subunit p40 / Cytotoxic lymphocyte maturation factor 40 kDa subunit / CLMF p40 / NK ...IL-12B / IL-12 subunit p40 / Cytotoxic lymphocyte maturation factor 40 kDa subunit / CLMF p40 / NK cell stimulatory factor chain 2 / NKSF2


Mass: 34739.945 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12B, NKSF2 / Cell line (production host): HEK 293 / Production host: HOMO SAPIENS (human) / References: UniProt: P29460
#3: Antibody USTEKINUMAB FAB LIGHT CHAIN


Mass: 23474.996 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Description: PAPAIN DIGESTED FROM mAb / Cell line (production host): HEK 293 / Production host: HOMO SAPIENS (human)
#4: Antibody USTEKINUMAB FAB HEAVY CHAIN


Mass: 24361.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Description: PAPAIN DIGESTED FROM mAb / Cell line (production host): HEK 293 / Production host: HOMO SAPIENS (human)

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Interleukin-12 subunit ... / Sugars / Non-polymers , 3 types, 46 molecules B

#2: Protein Interleukin-12 subunit alpha / IL-12A / IL-12 subunit p35 / Cytotoxic lymphocyte maturation factor 35 kDa subunit / CLMF p35 / NK ...IL-12A / IL-12 subunit p35 / Cytotoxic lymphocyte maturation factor 35 kDa subunit / CLMF p35 / NK cell stimulatory factor chain 1 / NKSF1


Mass: 22568.154 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL12A, NKSF1 / Cell line (production host): HEK 293 / Production host: HOMO SAPIENS (human) / References: UniProt: P29459
#5: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 44 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.79 Å3/Da / Density % sol: 55.88 %

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorDate: Jun 4, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→45.7 Å / Num. obs: 24337 / % possible obs: 99.9 % / Redundancy: 13.22 % / Rmerge(I) obs: 0.128
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
3-3.1114.070.49441100
3.11-3.2314.010.4114.51100
3.23-3.3813.90.3165.51100
3.38-3.5613.480.247.51100
3.56-3.7813.10.28.9199.8
3.78-4.0712.780.16410.5199.5
4.07-4.4812.540.1512.1198.8
4.48-5.1312.590.13714.5199.9
5.13-6.4613.210.12115.41100
6.46-45.712.570.07324.51100

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Processing

Software
NameVersionClassificationNB
d*TREK9.9.2Ldata processing
PHENIXrefinement
PDB_EXTRACT3.005data extraction
ADSCQuantumdata collection
d*TREKdata reduction
d*TREKdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→26.66 Å / Occupancy max: 1 / Occupancy min: 1 / SU ML: 1.23 / σ(F): 1.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.303 1168 4.83 %
Rwork0.211 --
obs0.215 24198 99.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 59.39 Å2 / ksol: 0.29 e/Å3
Displacement parametersBiso mean: 100.86 Å2
Baniso -1Baniso -2Baniso -3
1-15.628 Å20 Å2-0 Å2
2--0.364 Å2-0 Å2
3----15.992 Å2
Refinement stepCycle: LAST / Resolution: 3→26.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6973 0 61 44 7078
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0057205
X-RAY DIFFRACTIONf_angle_d0.8839777
X-RAY DIFFRACTIONf_dihedral_angle_d19.1682583
X-RAY DIFFRACTIONf_chiral_restr0.0591118
X-RAY DIFFRACTIONf_plane_restr0.0041229
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.1360.411510.3022840X-RAY DIFFRACTION100
3.136-3.3010.3881520.2892812X-RAY DIFFRACTION100
3.301-3.5080.3531400.262848X-RAY DIFFRACTION100
3.508-3.7780.3341460.2242844X-RAY DIFFRACTION100
3.778-4.1570.2871480.1982860X-RAY DIFFRACTION99
4.157-4.7550.2481520.1642856X-RAY DIFFRACTION99
4.755-5.980.2561600.1672902X-RAY DIFFRACTION100
5.98-26.660.2951190.213068X-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)
12.08790.23811.84214.36171.92744.4309-0.08420.1248-0.01070.61320.014-0.0155-0.43310.49690.04580.7661-0.1266-0.1090.61380.05540.501440.236411.410121.8434
20.57820.0825-1.49172.6773.27084.7470.01260.1033-0.02910.7286-0.05270.0542-0.1421-0.2535-0.0051.16080.0610.13090.57920.01640.613824.277218.46245.9179
30.7089-1.0589-0.8128-0.94571.24380.0284-0.77940.064-0.53220.00850.40820.24880.4356-0.11320.55131.42790.00690.48810.40180.08310.99966.284820.510970.7702
46.8954.8711-1.66326.0471-2.96551.9377-0.97540.2602-1.1064-0.8723-0.5144-0.7051-0.78510.2551.17791.8444-0.0198-0.39150.49820.09750.75641.649924.671132.4647
51.5731-0.4567-0.43814.352-0.56512.9995-0.8028-0.06-0.17040.06560.43920.91740.0667-0.29270.48521.2962-0.1802-0.06220.6079-0.06760.74516.227843.148263.4442
61.6603-0.6413-0.68512.10572.5461.55910.1685-0.0281-0.2174-0.23390.5931-0.0151.0091.2877-0.92291.44050.3111-0.19840.8602-0.14830.802435.270332.510766.9512
73.18122.0701-0.17116.956-0.7862-3.10650.168-0.7708-0.01812.5625-0.1399-1.04930.01950.4103-0.36191.93070.2467-0.4470.6441-0.05750.781833.822536.899482.9221
81.158-3.3968-0.54283.64990.48292.6928-0.07550.26170.2524-0.67980.4373-0.90340.19070.1156-0.3250.9282-0.0741-0.03320.3531-0.10990.702227.608650.919164.6824
9-0.3319-0.35050.05254.81440.4150.95880.0017-0.07620.05120.6176-0.1293-0.4799-0.4003-0.35560.04561.06680.1258-0.06240.6638-0.13930.740323.630451.316570.0004
102.2363-0.9530.08231.0660.1372-0.6303-0.15380.273-0.4680.96420.649-0.15510.39990.092-0.38091.22940.0947-0.0090.3661-0.13820.490224.870243.272462.325
112.04141.21581.7710.824-0.29668.6383-0.020.7511-0.2380.0872-0.0413-0.1041-0.77851.48590.05140.3517-0.2519-0.02170.7270.03620.400641.557216.1161-4.8753
122.1115-0.28370.0250.9012-0.1253.31150.02560.24720.0859-0.2440.1721-0.003-0.35390.3885-0.12480.7993-0.1069-0.03370.94270.04370.624725.583116.6882-37.5463
133.18670.9930.74011.2992-0.10187.35280.27750.1863-0.0310.1388-0.04370.20540.1152-0.8525-0.28310.292-0.0386-0.02240.38660.02920.375721.545910.12412.6415
143.6872-1.92541.90012.773-0.33953.86520.0010.0172-0.2664-0.79590.56440.22170.73620.3869-0.41460.7859-0.0394-0.06130.5601-0.04040.48520.15332.4783-31.6634
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND RESID 1:87
2X-RAY DIFFRACTION2CHAIN A AND RESID 88:212
3X-RAY DIFFRACTION3CHAIN A AND RESID 213:305
4X-RAY DIFFRACTION4CHAIN K
5X-RAY DIFFRACTION5CHAIN B AND RESID 12:44
6X-RAY DIFFRACTION6CHAIN B AND RESID 48:74
7X-RAY DIFFRACTION7CHAIN B AND RESID 79:98
8X-RAY DIFFRACTION8CHAIN B AND RESID 99:128
9X-RAY DIFFRACTION9CHAIN B AND RESID 129:156
10X-RAY DIFFRACTION10CHAIN B AND RESID 160:197
11X-RAY DIFFRACTION11CHAIN L AND RESID 1:109
12X-RAY DIFFRACTION12CHAIN L AND RESID 110:214
13X-RAY DIFFRACTION13CHAIN H AND RESID 1:119
14X-RAY DIFFRACTION14CHAIN H AND RESID 120:220

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