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- PDB-9q22: Crystal structure of ternary complex Helios-ZF2:I-19:CRBN:DDB1 -

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Basic information

Entry
Database: PDB / ID: 9q22
TitleCrystal structure of ternary complex Helios-ZF2:I-19:CRBN:DDB1
Components
  • DNA damage-binding protein 1
  • Protein cereblon
  • Zinc finger protein Helios
KeywordsLIGASE / CEREBLON / DEGRADER / HELIOS / IKZF2 / DDB1 / MOCLECULAR 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 / regulation of circadian rhythm / DNA Damage Recognition in GG-NER / 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 / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / DNA repair / apoptotic process / DNA damage response / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / protein-containing complex / extracellular space / DNA binding / extracellular exosome / zinc ion binding / nucleoplasm / metal ion binding / nucleus / membrane / cytoplasm / cytosol
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) / 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 / Zinc finger, C2H2 type / zinc finger / Zinc finger C2H2 type domain profile. / Zinc finger C2H2 superfamily / Zinc finger C2H2 type domain signature. / Zinc finger C2H2-type / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
: / 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: 3.406 Å
AuthorsZhu, J. / Pagarigan, B.E. / Tran, E.T.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J Med Chem / Year: 2025
Title: Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of Cereblon-Based Molecular Glues.
Authors: Guilian Luchini / Shuang Liu / Hannah L Powers / Emily Cherney / Jinyi Zhu / Kristina Danga / Joel W Thompson / Lihong Shi / Barbra Pagarigan / Dong Donna Wei / Peter Park / Andrew P Degnan ...Authors: Guilian Luchini / Shuang Liu / Hannah L Powers / Emily Cherney / Jinyi Zhu / Kristina Danga / Joel W Thompson / Lihong Shi / Barbra Pagarigan / Dong Donna Wei / Peter Park / Andrew P Degnan / Christoph W Zapf / Jennifer R Riggs / Scott Johnson / Thomas Cummins /
Abstract: Cullin-RING Ligase 4 Cereblon (CRL4) (CRBN) E3 ligase modulatory drugs (CELMoDs) make up a successful class of compounds targeting neosubstrates for proteasome-dependent degradation. Early ...Cullin-RING Ligase 4 Cereblon (CRL4) (CRBN) E3 ligase modulatory drugs (CELMoDs) make up a successful class of compounds targeting neosubstrates for proteasome-dependent degradation. Early immunomodulatory drugs (IMiDs) target Ikaros and Aiolos degradation. In addition, there are ongoing clinical trials targeting the degradation of biologically relevant proteins such as GSPT1, CK1α, and Helios with CRBN-based molecular glues. To date, most advanced preclinical and clinical CRBN-based molecular glues recruit their neosubstrates through canonical G-motifs, secondary protein features that are structurally similar but have significantly different amino acid sequence identities. Analogous to the development of kinase inhibitors, optimizing both neosubstrate recruitment and degradation selectivity is important to minimize potential off-target activity. Here, we describe a computational structure-based approach to analyze and predict putative ligand interactions important in the neosubstrate ternary complex. This approach provides valuable insights for enhanced designs toward the development of more selective and efficacious CRBN-based molecular glues.
History
DepositionAug 14, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 1, 2025Provider: repository / Type: Initial release
Revision 1.1Oct 22, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,7466
Polymers148,1823
Non-polymers5643
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6560 Å2
ΔGint-33 kcal/mol
Surface area49510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)260.240, 260.240, 123.660
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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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: 95773.695 Da / Num. of mol.: 1 / Fragment: UNP residues 1-381,706-1140
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Cell line (production host): High Five / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 48976.117 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Cell (production host): HIGH FIVE / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#3: Protein/peptide Zinc finger protein Helios / Ikaros family zinc finger protein 2


Mass: 3431.885 Da / Num. of mol.: 1 / Fragment: UNP residues 135-163
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF2, HELIOS, ZNFN1A2 / Plasmid: pMAL-c5x / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q9UKS7
#4: Chemical ChemComp-A1CNP / (3S)-3-[5-(1-benzyl-4-hydroxypiperidin-4-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione


Mass: 433.500 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N3O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / 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: 4.42 Å3/Da / Density % sol: 72.18 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.148 M lithium citrate, 0.1 M Tris, pH 7.5, 19.4% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 7, 2020
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.406→130.12 Å / Num. obs: 21894 / % possible obs: 94.9 % / Redundancy: 20.2 % / Biso Wilson estimate: 90.33 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.322 / Rpim(I) all: 0.073 / Rrim(I) all: 0.33 / Net I/σ(I): 7.7
Reflection shellResolution: 3.406→3.852 Å / Redundancy: 18.6 % / Rmerge(I) obs: 1.988 / Mean I/σ(I) obs: 2 / Num. unique obs: 1095 / CC1/2: 0.692 / Rpim(I) all: 0.462 / Rrim(I) all: 2.042 / % possible all: 67

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (20-MAY-2020)refinement
STARANISOdata scaling
XDSdata reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.406→130.12 Å / Cor.coef. Fo:Fc: 0.897 / Cor.coef. Fo:Fc free: 0.892 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.64
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.252 1083 4.95 %RANDOM
Rwork0.2203 ---
obs0.2218 21894 64 %-
Displacement parametersBiso mean: 167.37 Å2
Baniso -1Baniso -2Baniso -3
1--2.0641 Å20 Å20 Å2
2---2.0641 Å20 Å2
3---4.1282 Å2
Refine analyzeLuzzati coordinate error obs: 0.49 Å
Refinement stepCycle: LAST / Resolution: 3.406→130.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9397 0 34 0 9431
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.00918801HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0733962HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d5641SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes3054HARMONIC5
X-RAY DIFFRACTIONt_it9620HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.11
X-RAY DIFFRACTIONt_other_torsion17.18
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1280SEMIHARMONIC5
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_contact13063SEMIHARMONIC4
LS refinement shellResolution: 3.41→3.66 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.237 -5.94 %
Rwork0.2139 412 -
all0.2152 438 -
obs--6.64 %
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)
11.09210.4796-0.02711.6472-0.19731.6389-0.15780.0548-0.1622-0.3476-0.0393-0.00670.09140.00070.1971-0.1536-0.02350.16140.07820.0244-0.1764-12.9563110.5428-8.0407
21.68891.1467-1.60350.8264-1.4643.10390.3249-0.29780.1510.11-0.15440.1082-0.04580.1907-0.1705-0.14-0.27010.19910.14-0.0409-0.0733-26.5761101.076629.7308
35.7951.45520.977410.8359-2.79638.31550.0906-0.6695-0.28460.16930.0910.3571-0.1037-0.2085-0.1815-0.0831-0.22570.05820.08160.20310.049-41.390685.677350.9528
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }

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