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- PDB-9e2u: Crystal structure of DDB1-CRBN-ALV1 complex bound to triple ZnF o... -

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Entry
Database: PDB / ID: 9e2u
TitleCrystal structure of DDB1-CRBN-ALV1 complex bound to triple ZnF of Helios (IKZF2 ZF1-3)
Components
  • DNA damage-binding protein 1
  • Protein cereblon
  • Zinc finger protein Helios
KeywordsLIGASE / CRBN / DDB1 / IKZF2 / ALV1 / DEGRADATION / E3 LIGASE / MOLECULAR GLUE
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / 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 / Cul4-RING E3 ubiquitin ligase complex ...negative regulation of monoatomic ion transmembrane transport / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / epigenetic programming in the zygotic pronuclei / 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 / Cul4-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 / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER / Wnt signaling pathway / 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 / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / damaged DNA binding / transmembrane transporter binding / chromosome, telomeric region / protein ubiquitination / DNA repair / apoptotic process / DNA damage response / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / protein-containing complex / extracellular space / DNA binding / extracellular exosome / nucleoplasm / metal ion binding / nucleus / membrane / 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) / RSE1/DDB1/CPSF1 second beta-propeller ...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) / RSE1/DDB1/CPSF1 second beta-propeller / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / : / CPSF A subunit region / RSE1/DDB1/CPSF1 first beta-propeller / PUA-like superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Chem-RN9 / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 4.11 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
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA262188 United States
Citation
Journal: Mol Cell / Year: 2025
Title: Expanding the druggable zinc-finger proteome defines properties of drug-induced degradation.
Authors: Mikołaj Słabicki / Jiho Park / Radosław P Nowak / Shourya S Roy Burman / Jesse Pellman / Charles Zou / Hlib Razumkov / Jeannie Carreiro / Simran Rastogi / Anna Goldstein / Marek M Nagiec ...Authors: Mikołaj Słabicki / Jiho Park / Radosław P Nowak / Shourya S Roy Burman / Jesse Pellman / Charles Zou / Hlib Razumkov / Jeannie Carreiro / Simran Rastogi / Anna Goldstein / Marek M Nagiec / Katherine A Donovan / Jianwei Che / Moritz Hunkeler / Qixiang Geng / Chi-Lin Hsu / Megha Lakshminarayan / Chelsea Shu / Rebecca L Zon / Zuzanna Kozicka / Paul M C Park / Jonathan M Tsai / Hojong Yoon / Lyn H Jones / Adam S Sperling / Nathanael S Gray / Eric S Fischer / Benjamin L Ebert /
Abstract: Glutarimide analogs, such as thalidomide, redirect the E3 ubiquitin ligase CRL4 to induce degradation of certain zinc finger (ZF) proteins. Although the core structural motif recognized by CRBN has ...Glutarimide analogs, such as thalidomide, redirect the E3 ubiquitin ligase CRL4 to induce degradation of certain zinc finger (ZF) proteins. Although the core structural motif recognized by CRBN has been characterized, it does not fully explain substrate specificity. To explore the role of residues adjacent to this core motif, we constructed a comprehensive ZF reporter library of 9,097 reporters derived from 1,655 human ZF proteins and conducted a library-on-library screen with 29 glutarimide analogs to identify compounds that collectively degrade 38 ZF reporters. Cryo-electron microscopy and crystal structures of ZFs in complex with CRBN revealed the importance of interactions beyond the core ZF degron. We used systematic mutagenesis of ZFs and CRBN to identify modes of neosubstrate recruitment requiring distinct amino acids. Finally, we found subtle chemical variations in glutarimide analogs that alter target scope and selectivity, thus providing a roadmap for their rational design.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionOct 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 3, 2025Provider: repository / Type: Initial release

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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: DNA damage-binding protein 1
D: Protein cereblon
E: DNA damage-binding protein 1
F: Protein cereblon
G: DNA damage-binding protein 1
H: Protein cereblon
I: DNA damage-binding protein 1
J: Protein cereblon
K: DNA damage-binding protein 1
L: Protein cereblon
M: DNA damage-binding protein 1
N: Protein cereblon
O: DNA damage-binding protein 1
P: Protein cereblon
R: Zinc finger protein Helios
S: Zinc finger protein Helios
T: Zinc finger protein Helios
U: Zinc finger protein Helios
V: Zinc finger protein Helios
W: Zinc finger protein Helios
X: Zinc finger protein Helios
Y: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,363,48661
Polymers1,357,63024
Non-polymers5,85637
Water00
1
I: DNA damage-binding protein 1
J: Protein cereblon
Y: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,4608
Polymers169,7043
Non-polymers7575
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: DNA damage-binding protein 1
B: Protein cereblon
T: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,4608
Polymers169,7043
Non-polymers7575
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: DNA damage-binding protein 1
D: Protein cereblon
W: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,3957
Polymers169,7043
Non-polymers6914
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
E: DNA damage-binding protein 1
F: Protein cereblon
S: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,4608
Polymers169,7043
Non-polymers7575
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
G: DNA damage-binding protein 1
H: Protein cereblon
V: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,3957
Polymers169,7043
Non-polymers6914
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
K: DNA damage-binding protein 1
L: Protein cereblon
U: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,3957
Polymers169,7043
Non-polymers6914
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
7
M: DNA damage-binding protein 1
N: Protein cereblon
R: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,4608
Polymers169,7043
Non-polymers7575
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
8
O: DNA damage-binding protein 1
P: Protein cereblon
X: Zinc finger protein Helios
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,4608
Polymers169,7043
Non-polymers7575
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)208.590, 279.059, 286.298
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: 96425.586 Da / Num. of mol.: 8
Fragment: internal deletion of the BPB domain,internal deletion of the BPB domain
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: 53005.207 Da / Num. of mol.: 8
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
Zinc finger protein Helios


Mass: 20272.938 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Details: MDWSHPQFEKSAVGLNDIFEAQKIEWHEGGGGSGENLYFQGG is the StrepII Avi TEV cleavable tag. Construct encompasses 3 ZnF domains. The C-terminal tail that is not visible
Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF2 / Production host: Trichoplusia ni (cabbage looper)
#4: 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.: 8 / Source method: obtained synthetically / Formula: C25H23ClN4O5 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical...
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 29 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestY
Has protein modificationN

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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: 3.07 Å3/Da / Density % sol: 59.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 20.455% PEG 3350, 0.214 M Li3 Cit

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 11, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 4.11→168.59 Å / Num. obs: 130289 / % possible obs: 100 % / Redundancy: 9.3 % / Biso Wilson estimate: 187.98 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.146 / Rpim(I) all: 0.074 / Rrim(I) all: 0.165 / Net I/σ(I): 9.4
Reflection shellResolution: 4.11→4.18 Å / Redundancy: 9.8 % / Rmerge(I) obs: 2.569 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 6391 / CC1/2: 0.37 / Rpim(I) all: 1.282 / Rrim(I) all: 2.878 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
RAPDdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 4.11→69.33 Å / SU ML: 0.6789 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 32.9451
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2889 6413 4.94 %
Rwork0.2349 123423 -
obs0.2376 129836 99.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 213.85 Å2
Refinement stepCycle: LAST / Resolution: 4.11→69.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms81300 0 309 0 81609
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002483231
X-RAY DIFFRACTIONf_angle_d0.4938112705
X-RAY DIFFRACTIONf_chiral_restr0.041912674
X-RAY DIFFRACTIONf_plane_restr0.004214632
X-RAY DIFFRACTIONf_dihedral_angle_d13.265731080
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
4.11-4.160.38812100.37113994X-RAY DIFFRACTION97.74
4.16-4.210.3712080.34834030X-RAY DIFFRACTION99.41
4.21-4.260.40111960.32514124X-RAY DIFFRACTION99.68
4.26-4.310.3481770.31284067X-RAY DIFFRACTION99.93
4.31-4.370.33562060.29544104X-RAY DIFFRACTION100
4.37-4.430.36312010.28894106X-RAY DIFFRACTION99.98
4.43-4.490.33891930.28594080X-RAY DIFFRACTION99.98
4.49-4.560.31532060.28024117X-RAY DIFFRACTION99.93
4.56-4.630.30612020.26564083X-RAY DIFFRACTION99.98
4.63-4.70.32512190.25724075X-RAY DIFFRACTION99.95
4.7-4.790.31992380.24734083X-RAY DIFFRACTION99.93
4.79-4.870.2972400.24624061X-RAY DIFFRACTION99.88
4.87-4.970.30981990.25854122X-RAY DIFFRACTION99.95
4.97-5.070.32342620.26934059X-RAY DIFFRACTION99.93
5.07-5.180.33192150.2624083X-RAY DIFFRACTION100
5.18-5.30.31171990.25554113X-RAY DIFFRACTION99.95
5.3-5.430.32532040.24344106X-RAY DIFFRACTION100
5.43-5.580.32032200.23744102X-RAY DIFFRACTION100
5.58-5.740.33031920.24314126X-RAY DIFFRACTION99.95
5.74-5.930.33332140.24524126X-RAY DIFFRACTION100
5.93-6.140.33812140.24344144X-RAY DIFFRACTION99.98
6.14-6.380.30562170.23554102X-RAY DIFFRACTION99.98
6.38-6.670.31382200.23744142X-RAY DIFFRACTION99.95
6.67-7.030.30142330.23114122X-RAY DIFFRACTION100
7.03-7.470.26292110.21934156X-RAY DIFFRACTION100
7.47-8.040.27432030.2214184X-RAY DIFFRACTION99.91
8.04-8.850.26332290.20074157X-RAY DIFFRACTION99.93
8.85-10.130.19832170.16764185X-RAY DIFFRACTION99.86
10.13-12.740.19632160.16534188X-RAY DIFFRACTION98.5
12.75-69.330.32282520.26854282X-RAY DIFFRACTION97.63
Refinement TLS params.Method: refined / Origin x: -116.907381677 Å / Origin y: 56.0573213676 Å / Origin z: -64.3177157953 Å
111213212223313233
T1.52800505824 Å20.0398618386473 Å20.00484071266804 Å2-1.48057167073 Å20.0373845226401 Å2--1.53287663911 Å2
L0.120774822339 °20.0259615198778 °2-0.0155669869148 °2-0.091331238026 °20.00128805159898 °2--0.155219038506 °2
S0.0397486832879 Å °0.0225362408117 Å °0.0903275579325 Å °-0.0207183825408 Å °0.00860720619903 Å °-0.0120915915642 Å °0.0108841009573 Å °0.021926014688 Å °-0.0376546740036 Å °
Refinement TLS groupSelection details: all

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