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- PDB-6vwu: X-ray structure of ALKS 4230, a fusion of circularly permuted hum... -

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Basic information

Entry
Database: PDB / ID: 6vwu
TitleX-ray structure of ALKS 4230, a fusion of circularly permuted human Interleukin-2 and Interleukin-2 Receptor alpha
ComponentsInterleukin-2,Interleukin-2 receptor subunit alpha
KeywordsCYTOKINE / circular permutation / ALKS 4230
Function / homology
Function and homology information


regulation of T cell tolerance induction / interleukin-2 receptor complex / interleukin-2 receptor activity / interleukin-2 binding / kappa-type opioid receptor binding / regulation of CD4-positive, alpha-beta T cell proliferation / regulation of T cell homeostatic proliferation / interleukin-2 receptor binding / positive regulation of plasma cell differentiation / response to tacrolimus ...regulation of T cell tolerance induction / interleukin-2 receptor complex / interleukin-2 receptor activity / interleukin-2 binding / kappa-type opioid receptor binding / regulation of CD4-positive, alpha-beta T cell proliferation / regulation of T cell homeostatic proliferation / interleukin-2 receptor binding / positive regulation of plasma cell differentiation / response to tacrolimus / glycosphingolipid binding / negative regulation of lymphocyte proliferation / positive regulation of tissue remodeling / negative regulation of T-helper 17 cell differentiation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / leukocyte activation involved in immune response / positive regulation of isotype switching to IgG isotypes / interleukin-2-mediated signaling pathway / activated T cell proliferation / natural killer cell activation / positive regulation of regulatory T cell differentiation / : / kinase activator activity / inflammatory response to antigenic stimulus / negative regulation of B cell apoptotic process / Interleukin-2 signaling / positive regulation of T cell differentiation / positive regulation of immunoglobulin production / positive regulation of dendritic spine development / activation-induced cell death of T cells / positive regulation of activated T cell proliferation / positive regulation of interleukin-17 production / T cell differentiation / Interleukin receptor SHC signaling / negative regulation of T cell proliferation / positive regulation of B cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / Notch signaling pathway / extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of protein phosphorylation / cytokine activity / growth factor activity / negative regulation of inflammatory response / positive regulation of inflammatory response / positive regulation of type II interferon production / cell-cell signaling / positive regulation of cytosolic calcium ion concentration / RAF/MAP kinase cascade / positive regulation of cell growth / carbohydrate binding / response to ethanol / adaptive immune response / transcription by RNA polymerase II / cell surface receptor signaling pathway / cell adhesion / inflammatory response / immune response / external side of plasma membrane / apoptotic process / positive regulation of cell population proliferation / negative regulation of apoptotic process / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / plasma membrane
Similarity search - Function
Interleukin-2 receptor alpha / Interleukin-2 / Interleukin-2, conserved site / Interleukin 2 / Interleukin-2 signature. / Interleukin-2 family / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. ...Interleukin-2 receptor alpha / Interleukin-2 / Interleukin-2, conserved site / Interleukin 2 / Interleukin-2 signature. / Interleukin-2 family / Sushi repeat (SCR repeat) / Domain abundant in complement control proteins; SUSHI repeat; short complement-like repeat (SCR) / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Four-helical cytokine-like, core
Similarity search - Domain/homology
Interleukin-2 receptor subunit alpha / Interleukin-2 / Interleukin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.4 Å
AuthorsLosey, H.C.
CitationJournal: J Immunother Cancer / Year: 2020
Title: ALKS 4230: a novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy.
Authors: Lopes, J.E. / Fisher, J.L. / Flick, H.L. / Wang, C. / Sun, L. / Ernstoff, M.S. / Alvarez, J.C. / Losey, H.C.
History
DepositionFeb 20, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 6, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_id_ISSN / _citation.journal_volume ..._citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model
Item: _citation.country / _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-2,Interleukin-2 receptor subunit alpha


Theoretical massNumber of molelcules
Total (without water)34,4641
Polymers34,4641
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.809, 86.809, 119.576
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

#1: Protein Interleukin-2,Interleukin-2 receptor subunit alpha / IL-2 / IL-2 / T-cell growth factor / TCGF / IL2-RA / TAC antigen / p55


Mass: 34464.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IL2, IL2RA / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: Q6QWN0, UniProt: P60568, UniProt: P01589

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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: 3.77 Å3/Da / Density % sol: 67.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: An equal volume of protein was mixed with crystallization buffer, 25 % (w/v) PEG 3350, 0.2 M MgCl2, 0.1 M Hepes 7.5. Large crystals appeared within 48-72 hours, and were frozen in a ...Details: An equal volume of protein was mixed with crystallization buffer, 25 % (w/v) PEG 3350, 0.2 M MgCl2, 0.1 M Hepes 7.5. Large crystals appeared within 48-72 hours, and were frozen in a cryoprotectant consisting of mother liquor with 10 % glycerol
Temp details: room temperature

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1 Å
DetectorType: RDI CMOS_8M / Detector: CMOS / Date: Aug 12, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.4→63.645 Å / Num. obs: 7538 / % possible obs: 100 % / Redundancy: 10.9 % / Rmerge(I) obs: 0.185 / Net I/σ(I): 12.8
Reflection shellResolution: 3.4→3.522 Å / Rmerge(I) obs: 0.185 / Num. unique obs: 750 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIXdev_1951refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1Z92

1z92


Resolution: 3.4→63.645 Å / SU ML: 0.74 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 46.93
RfactorNum. reflection% reflection
Rfree0.2973 421 5.6 %
Rwork0.2754 --
obs0.2768 7517 99.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 306.76 Å2 / Biso mean: 171.9539 Å2 / Biso min: 79.59 Å2
Refinement stepCycle: final / Resolution: 3.4→63.645 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2057 0 0 0 2057
Num. residues----258
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0022106
X-RAY DIFFRACTIONf_angle_d0.6542846
X-RAY DIFFRACTIONf_chiral_restr0.03313
X-RAY DIFFRACTIONf_plane_restr0.003361
X-RAY DIFFRACTIONf_dihedral_angle_d15.152805
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
3.4003-3.89230.4491410.40542311
3.8923-4.90360.30761440.26882330
4.9036-63.6450.27721360.23142455
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)
10.0039-0.06780.01010.0488-0.0411-0.00430.1808-0.1242-0.51370.2153-0.10270.2779-0.1763-0.1797-01.1089-0.27540.02461.40690.03661.158-73.6912101.392431.1216
20.2983-0.0220.29570.41-0.11080.24940.1465-0.08470.14760.0112-0.20720.06020.48630.90800.9298-0.00240.10890.93960.02310.902-63.170295.911835.4087
30.0390.03940.0926-0.0447-0.00740.08630.2046-0.3101-0.779-0.46640.3764-0.56180.3964-0.062301.275-0.4368-0.05361.3152-0.18361.2079-70.907491.903732.997
40.34230.1188-0.07690.1590.50220.2291-0.35371.60524.3502-2.9794-1.51330.6876-3.2224-1.17020-0.7991-1.74691.59520.4802-0.4221-1.0532-80.222487.575458.3227
50.10070.13590.28250.2580.23460.13840.19260.15690.2026-0.59170.27350.18860.02670.0977-01.8943-0.26130.02191.1196-0.03411.192-83.212283.734243.5191
6-0.0165-0.0157-0.14420.0213-0.0785-0.0397-0.4594-0.372-0.33440.09430.0872-0.3924-0.2111-0.237101.5836-0.3029-0.07961.22410.20762.1699-81.754676.124245.2196
7-0.0069-0.0930.01920.06470.04120.03630.3323-0.2074-0.341-0.36110.3685-0.25730.1146-0.043401.3425-0.05630.0731.01740.02061.1586-83.58179.241764.1216
80.01350.0779-0.06060.03930.06570.11240.16290.12210.42150.14540.30290.50960.17980.6522-01.7152-0.23890.11381.13780.0421.225-82.131789.317167.1503
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 23 )A3 - 23
2X-RAY DIFFRACTION2chain 'A' and (resid 24 through 110 )A24 - 110
3X-RAY DIFFRACTION3chain 'A' and (resid 111 through 130 )A111 - 130
4X-RAY DIFFRACTION4chain 'A' and (resid 131 through 155 )A131 - 155
5X-RAY DIFFRACTION5chain 'A' and (resid 156 through 198 )A156 - 198
6X-RAY DIFFRACTION6chain 'A' and (resid 199 through 254 )A199 - 254
7X-RAY DIFFRACTION7chain 'A' and (resid 255 through 281 )A255 - 281
8X-RAY DIFFRACTION8chain 'A' and (resid 282 through 303 )A282 - 303

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