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- PDB-7lps: Crystal structure of DDB1-CRBN-ALV1 complex bound to Helios (IKZF... -

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Basic information

Entry
Database: PDB / ID: 7lps
TitleCrystal structure of DDB1-CRBN-ALV1 complex bound to Helios (IKZF2 ZF2)
Components
  • DNA damage-binding protein 1
  • Protein cereblon
  • Zinc finger protein Helios
KeywordsLIGASE / CRBN / DDB1 / IKZF2 / ALV / Degradation / E3 ligase
Function / homology
Function and homology information


negative regulation of large conductance calcium-activated potassium channel activity / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex ...negative regulation of large conductance calcium-activated potassium channel activity / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of reproductive process / negative regulation of developmental process / locomotory exploration behavior / cullin family protein binding / viral release from host cell / positive regulation of Wnt signaling pathway / ectopic germ cell programmed cell death / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / proteasomal protein catabolic process / positive regulation of gluconeogenesis / nucleotide-excision repair / positive regulation of protein-containing complex assembly / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Dual Incision in GG-NER / Formation of TC-NER Pre-Incision Complex / Wnt signaling pathway / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / Neddylation / site of double-strand break / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / Potential therapeutics for SARS / damaged DNA binding / chromosome, telomeric region / protein ubiquitination / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / DNA repair / DNA damage response / apoptotic process / regulation of transcription by RNA polymerase II / protein-containing complex binding / negative regulation of apoptotic process / nucleolus / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / nucleus / membrane / metal ion binding / cytosol / cytoplasm
Similarity search - Function
: / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) ...: / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / RSE1/DDB1/CPSF1 first beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / : / CPSF A subunit region / PUA-like superfamily / Zinc finger, C2H2 type / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / YVTN repeat-like/Quinoprotein amine dehydrogenase / Zinc finger C2H2-type / 7 Propeller / Methylamine Dehydrogenase; Chain H / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-RN9 / DNA damage-binding protein 1 / Protein cereblon / Zinc finger protein Helios
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.78 Å
AuthorsNowak, R.P. / Fischer, E.S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA214608 United States
Damon Runyon Cancer Research FoundationDRR-50-18 United States
CitationJournal: Nat.Chem.Biol. / Year: 2021
Title: Acute pharmacological degradation of Helios destabilizes regulatory T cells.
Authors: Wang, E.S. / Verano, A.L. / Nowak, R.P. / Yuan, J.C. / Donovan, K.A. / Eleuteri, N.A. / Yue, H. / Ngo, K.H. / Lizotte, P.H. / Gokhale, P.C. / Gray, N.S. / Fischer, E.S.
History
DepositionFeb 12, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1Jun 9, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _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: DNA damage-binding protein 1
B: Protein cereblon
C: Zinc finger protein Helios
D: DNA damage-binding protein 1
E: Protein cereblon
F: Zinc finger protein Helios
G: DNA damage-binding protein 1
H: Protein cereblon
I: Zinc finger protein Helios
J: DNA damage-binding protein 1
K: Protein cereblon
L: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)703,33724
Polymers700,83412
Non-polymers2,50312
Water00
1
A: DNA damage-binding protein 1
B: Protein cereblon
C: Zinc finger protein Helios
hetero molecules


  • defined by author
  • Evidence: fluorescence resonance energy transfer, TR-FRET dimerization assay performed between CRBN-DDB1 and IKZF2 ZnF2 by titrating in ALV1. Dose dependent increase of signal indicating complex ...Evidence: fluorescence resonance energy transfer, TR-FRET dimerization assay performed between CRBN-DDB1 and IKZF2 ZnF2 by titrating in ALV1. Dose dependent increase of signal indicating complex formation was observed., gel filtration, Size exclusion chromatography of CRBN-DDB1 indicated monomeric form of the CRBN-DDB1 protein., gel filtration, Size exclusion chromatography of IKZF2 ZnF2 indicated monomeric form of the IKZF2 ZnF2 protein.
  • 176 kDa, 3 polymers
  • Search similar-shape structures of this assembly by Omokage search (details)
Theoretical massNumber of molelcules
Total (without water)175,8346
Polymers175,2093
Non-polymers6263
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
D: DNA damage-binding protein 1
E: Protein cereblon
F: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,8346
Polymers175,2093
Non-polymers6263
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
G: DNA damage-binding protein 1
H: Protein cereblon
I: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,8346
Polymers175,2093
Non-polymers6263
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
J: DNA damage-binding protein 1
K: Protein cereblon
L: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,8346
Polymers175,2093
Non-polymers6263
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)151.800, 117.292, 196.713
Angle α, β, γ (deg.)90.00, 97.30, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
DNA damage-binding protein 1 / DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / ...DDB p127 subunit / DNA damage-binding protein a / DDBa / Damage-specific DNA-binding protein 1 / HBV X-associated protein 1 / XAP-1 / UV-damaged DNA-binding factor / UV-damaged DNA-binding protein 1 / UV-DDB 1 / XPE-binding factor / XPE-BF / Xeroderma pigmentosum group E-complementing protein / XPCe


Mass: 127097.469 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q16531
#2: Protein
Protein cereblon


Mass: 44867.398 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q96SW2
#3: Protein/peptide
Zinc finger protein Helios / Ikaros family zinc finger protein 2


Mass: 3243.704 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF2, HELIOS, ZNFN1A2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9UKS7
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-RN9 / 3-[3-[[1-[(3~{S})-2,6-bis(oxidanylidene)piperidin-3-yl]-2,5-bis(oxidanylidene)pyrrol-3-yl]amino]phenyl]-~{N}-(3-chloranyl-4-methyl-phenyl)propanamide


Mass: 494.927 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H23ClN4O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: 2.48 Å3/Da / Density % sol: 50.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8.57 / Details: 30% (w/v) PEG3350, 0.1 M Tris pH 8.57

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-C / Wavelength: 0.9792 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jul 12, 2019
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 3.78→150.57 Å / Num. obs: 67972 / % possible obs: 98.2 % / Redundancy: 4.6 % / Biso Wilson estimate: 82.75 Å2 / CC1/2: 0.988 / Rmerge(I) obs: 0.367 / Rpim(I) all: 0.286 / Net I/σ(I): 3.2
Reflection shellResolution: 3.78→3.86 Å / Redundancy: 4.5 % / Rmerge(I) obs: 1.813 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 4033 / CC1/2: 0.28 / Rpim(I) all: 1.439 / % possible all: 87.6

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (11-DEC-2020)refinement
XDSVERSION Mar 15, 2019 BUILT=20190315data reduction
Aimless0.5.32data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5fqd

5fqd


Resolution: 3.78→150.57 Å / Cor.coef. Fo:Fc: 0.89 / Cor.coef. Fo:Fc free: 0.87 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.827
RfactorNum. reflection% reflectionSelection details
Rfree0.3031 3410 5.07 %RANDOM
Rwork0.2887 ---
obs0.2895 67299 97.6 %-
Displacement parametersBiso mean: 124.3 Å2
Baniso -1Baniso -2Baniso -3
1--2.5162 Å20 Å20.5111 Å2
2---3.1434 Å20 Å2
3---5.6596 Å2
Refine analyzeLuzzati coordinate error obs: 0.67 Å
Refinement stepCycle: LAST / Resolution: 3.78→150.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms37402 0 148 0 37550
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00438294HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.751900HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d13312SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes6476HARMONIC5
X-RAY DIFFRACTIONt_it38142HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.01
X-RAY DIFFRACTIONt_other_torsion16.27
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion5048SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact24428SEMIHARMONIC4
LS refinement shellResolution: 3.78→3.82 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.4572 -4.9 %
Rwork0.3808 1280 -
all0.3846 1346 -
obs--64.47 %
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)
10.6612-0.54090.14780.7704-0.11760.36520.1850.07410.11-0.0072-0.0547-0.08360.139-0.0452-0.13040.14420.056-0.097-0.05550.06630.281772.052112.0052-14.2263
20.1936-0.0094-0.23680.1983-0.04491.50460.0427-0.11130.011-0.16730.05370.1643-0.0920.0307-0.09640.20180.0511-0.13710.00140.00490.270564.412912.12126.3687
38.5025-2.7285-0.32838.14572.58451.5977-0.22990.14350.3505-0.5109-0.0072-0.29490.4991-0.53030.23710.170.1348-0.1691-0.1195-0.04240.262870.83119.162454.9437
40.02730.2035-0.134900.04840.44250.1987-0.121-0.0620.2397-0.2528-0.0812-0.1127-0.40990.05410.1642-0.1419-0.16140.3040.05060.197213.790446.071116.7248
51.24940.22360.120500.03241.12380.2165-0.20340.1116-0.1708-0.1055-0.04320.16160.0213-0.1110.12560.0551-0.14380.00610.16030.267624.669846.433-23.2006
60.0333.2568-0.13916.9591-2.51681.8907-0.14690.53530.0591-0.5685-0.05230.47580.50780.10480.19920.0960.0063-0.0642-0.07250.1540.290924.773156.5579-50.6647
70.75040.17530.08590.9995-0.20030.06440.1511-0.10190.06220.07050.0220.14220.03870.0571-0.17310.1762-0.09880.0142-0.1462-0.05120.3097-8.848710.6893111.9342
80.4843-0.0239-0.39140.41030.21251.50830.08780.08180.0039-0.01060.05390.07760.00980.0919-0.14170.1324-0.059-0.14150.02540.00830.2705-0.509110.800871.5421
97.24821.79712.53223.5782-2.70398.9820.0580.1408-0.4522-0.2310.01660.51910.5628-0.4557-0.07470.1416-0.1326-0.15370.1237-0.1610.1155-6.12098.603842.6348
101.03110.2370.10030.78820.44340.2644-0.08220.0999-0.0037-0.0380.0348-0.0614-0.0702-0.02690.04740.05850.0134-0.056-0.06170.02910.293648.616742.608981.784
110.5803-0.0628-0.27940.0006-0.11081.39910.0994-0.01290.02810.1-0.14770.07530.1878-0.04450.04840.227-0.0847-0.0419-0.1148-0.10220.294538.219945.5493121.4284
122.7229-3.2568-2.56158.31482.5168-0.70130.0638-0.54820.5046-0.4840.1478-0.5050.5968-0.0042-0.2116-0.0798-0.0129-0.07260.0706-0.15490.291737.759556.4469148.6659
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ E|* }
6X-RAY DIFFRACTION6{ F|* }
7X-RAY DIFFRACTION7{ G|* }
8X-RAY DIFFRACTION8{ H|* }
9X-RAY DIFFRACTION9{ I|* }
10X-RAY DIFFRACTION10{ J|* }
11X-RAY DIFFRACTION11{ K|* }
12X-RAY DIFFRACTION12{ L|* }

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