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- PDB-8oiz: Crystal structure of human CRBN-DDB1 in complex with Pomalidomide -

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Basic information

Entry
Database: PDB / ID: 8oiz
TitleCrystal structure of human CRBN-DDB1 in complex with Pomalidomide
Components
  • DNA damage-binding protein 1
  • Protein cereblon
KeywordsPROTEIN BINDING / E3-ligase / Degradation / Glue / Protac
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / 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 monoatomic ion transmembrane transport / 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 / positive regulation of Wnt signaling pathway / viral release from host cell / ectopic germ cell programmed cell death / negative regulation of protein-containing complex assembly / positive regulation of viral genome replication / positive regulation of gluconeogenesis / proteasomal protein catabolic process / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / positive regulation of protein-containing complex assembly / 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 / 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 / protein-macromolecule adaptor activity / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / chromosome, telomeric region / damaged DNA binding / protein ubiquitination / DNA repair / apoptotic process / DNA damage response / protein-containing complex binding / nucleolus / negative regulation of apoptotic process / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / extracellular exosome / nucleoplasm / membrane / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon protease, N-terminal domain superfamily / Lon N-terminal domain profile. / Lon protease, N-terminal domain / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / Cleavage/polyadenylation specificity factor, A subunit, N-terminal ...Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / CULT domain / CULT domain profile. / Lon protease, N-terminal domain superfamily / Lon N-terminal domain profile. / Lon protease, N-terminal domain / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / Cleavage/polyadenylation specificity factor, A subunit, N-terminal / Mono-functional DNA-alkylating methyl methanesulfonate N-term / Cleavage/polyadenylation specificity factor, A subunit, C-terminal / CPSF A subunit region / PUA-like superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
S-Pomalidomide / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 Å
AuthorsLe Bihan, Y.-V. / Cabry, M.P. / van Montfort, R.L.M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKC309/A11566 United Kingdom
CitationJournal: Chembiochem / Year: 2023
Title: A Degron Blocking Strategy Towards Improved CRL4 CRBN Recruiting PROTAC Selectivity.
Authors: Bouguenina, H. / Scarpino, A. / O'Hanlon, J.A. / Warne, J. / Wang, H.Z. / Wah Hak, L.C. / Sadok, A. / McAndrew, P.C. / Stubbs, M. / Pierrat, O.A. / Hahner, T. / Cabry, M.P. / Le Bihan, Y.V. ...Authors: Bouguenina, H. / Scarpino, A. / O'Hanlon, J.A. / Warne, J. / Wang, H.Z. / Wah Hak, L.C. / Sadok, A. / McAndrew, P.C. / Stubbs, M. / Pierrat, O.A. / Hahner, T. / Cabry, M.P. / Le Bihan, Y.V. / Mitsopoulos, C. / Sialana, F.J. / Roumeliotis, T.I. / Burke, R. / van Montfort, R.L.M. / Choudhari, J. / Chopra, R. / Caldwell, J.J. / Collins, I.
History
DepositionMar 23, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 19, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author / diffrn_source
Item: _citation.journal_volume / _citation.title ..._citation.journal_volume / _citation.title / _citation_author.identifier_ORCID / _citation_author.name / _diffrn_source.pdbx_synchrotron_site

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,59510
Polymers174,8842
Non-polymers7118
Water8,809489
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5310 Å2
ΔGint-17 kcal/mol
Surface area60000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.841, 128.508, 198.377
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 2 molecules AB

#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: 128139.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 46744.746 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Plasmid: pFastBac / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2

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Non-polymers , 4 types, 497 molecules

#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-Y70 / S-Pomalidomide


Mass: 273.244 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H11N3O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 489 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.39 Å3/Da / Density % sol: 48.5 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8.2
Details: 0.8 microliter of CRBN-DDB1 complex at 25 mg/mL (including 1 mM compound and 2 % DMSO final) plus 0.8 microliter of a crystallisation solution consisting of 0.1 M Hepes pH 8.2, 0.2 M NaCl ...Details: 0.8 microliter of CRBN-DDB1 complex at 25 mg/mL (including 1 mM compound and 2 % DMSO final) plus 0.8 microliter of a crystallisation solution consisting of 0.1 M Hepes pH 8.2, 0.2 M NaCl and 10-16 % PEG Smear Medium, plus 0.2 microliter of seeds (established from the same conditions), against 500 microliter of crystallisation solution.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jan 27, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.5→49.59 Å / Num. obs: 64474 / % possible obs: 100 % / Redundancy: 13.2 % / Biso Wilson estimate: 67.44 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.236 / Rpim(I) all: 0.067 / Rrim(I) all: 0.246 / Net I/σ(I): 6.7 / Num. measured all: 851075 / Scaling rejects: 2029
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.5-2.5613.13.3035888645090.4570.9473.4370.799.8
11.46-49.5910.50.07982017780.9830.0250.08317.998.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (17-FEB-2023)refinement
Aimless0.7.3data scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→49.59 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.909 / SU R Cruickshank DPI: 0.439 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.459 / SU Rfree Blow DPI: 0.278 / SU Rfree Cruickshank DPI: 0.279
RfactorNum. reflection% reflectionSelection details
Rfree0.2615 3287 5.11 %RANDOM
Rwork0.2133 ---
obs0.2158 64384 100 %-
Displacement parametersBiso max: 137.97 Å2 / Biso mean: 67.13 Å2 / Biso min: 17.69 Å2
Baniso -1Baniso -2Baniso -3
1-11.7034 Å20 Å20 Å2
2---11.1786 Å20 Å2
3----0.5248 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: final / Resolution: 2.5→49.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11156 0 45 491 11692
Biso mean--57.72 62.82 -
Num. residues----1494
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d3803SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1964HARMONIC5
X-RAY DIFFRACTIONt_it11510HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1580SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies12HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8767SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d11510HARMONIC20.007
X-RAY DIFFRACTIONt_angle_deg15641HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion2.92
X-RAY DIFFRACTIONt_other_torsion18.16
LS refinement shellResolution: 2.5→2.52 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3353 52 4.04 %
Rwork0.3525 1236 -
all0.3517 1288 -
obs--99.38 %
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)
10.3112-0.0482-0.09920.3374-0.18930.73370.0124-0.0026-0.00030.0464-0.03550.06760.08380.00950.0231-0.0441-0.00430.01720.0211-0.0507-0.061-22.97813.6535-35.6091
22.7405-1.25390.56972.4550.50961.68620.01990.07870.221-0.2557-0.0998-0.0271-0.3445-0.22940.08-0.06260.1108-0.02120.1149-0.0245-0.2115-36.183515.2683-91.7422
31.10820.4187-0.11220.4525-0.00220.40950.0075-0.02320.1277-0.02410.06320.0231-0.08230.0092-0.0708-0.09980.01510.0198-0.0162-0.0275-0.022-14.491229.3956-51.8944
41.85040.40581.42860.95331.03842.7224-0.0454-0.1458-0.08410.0048-0.30450.1201-0.0395-0.30530.3499-0.0704-0.022-0.01750.0083-0.1247-0.0883-8.067748.8025-5.9658
50.48730.08390.51992.58091.47910.8335-0.0591-0.0554-0.05050.26830.0315-0.16520.0999-0.02750.0275-0.0002-0.01-0.03290.05-0.0554-0.1133-4.446131.615-26.6222
62.70260.80940.96661.27110.24360.64340.0740.1219-0.19060.0128-0.0517-0.0854-0.07210.0777-0.0223-0.0504-0.0173-0.03060.0829-0.0361-0.163913.658848.9494-12.5518
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{A|1 - 403}A1 - 403
2X-RAY DIFFRACTION2{A|404 - 708}A404 - 708
3X-RAY DIFFRACTION3{A|709 - 1148}A709 - 1148
4X-RAY DIFFRACTION4{B|44 - 163}B44 - 163
5X-RAY DIFFRACTION5{B|164 - 317}B164 - 317
6X-RAY DIFFRACTION6{B|318 - 442}B318 - 442

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