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- PDB-4tz4: Crystal Structure of Human Cereblon in Complex with DDB1 and Lena... -

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Basic information

Entry
Database: PDB / ID: 4tz4
TitleCrystal Structure of Human Cereblon in Complex with DDB1 and Lenalidomide
Components
  • DNA damage-binding protein 1
  • Protein cereblon
KeywordsDNA Binding Protein/Ligase / DCAF / DNA Binding Protein-Ligase complex
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 / locomotory exploration behavior / negative regulation of reproductive process / negative regulation of developmental process / cullin family protein binding / positive regulation of Wnt signaling pathway / viral release from host cell / ectopic germ cell programmed cell death / positive regulation of viral genome replication / negative regulation of protein-containing complex assembly / positive regulation of gluconeogenesis / proteasomal protein catabolic process / Recognition of DNA damage by PCNA-containing replication complex / nucleotide-excision repair / positive regulation of protein-containing complex assembly / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / regulation of circadian rhythm / 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 / damaged DNA binding / chromosome, telomeric region / 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
Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1480 / LON domain-like / Peptide methionine sulfoxide reductase. / DNA polymerase; domain 1 - #910 / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / Metal Binding Protein, Guanine Nucleotide Exchange Factor; Chain A / Archaeosine Trna-guanine Transglycosylase; Chain: A, domain 4 / CULT domain / CULT domain profile. ...Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1480 / LON domain-like / Peptide methionine sulfoxide reductase. / DNA polymerase; domain 1 - #910 / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / Metal Binding Protein, Guanine Nucleotide Exchange Factor; Chain A / Archaeosine Trna-guanine Transglycosylase; Chain: A, domain 4 / 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 / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Beta Complex / DNA polymerase; domain 1 / Roll / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Up-down Bundle / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
S-Lenalidomide / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.01 Å
AuthorsChamberlain, P.P. / Pagarigan, B. / Delker, S. / Leon, B. / Riley, M.
CitationJournal: To Be Published
Title: Structural Basis for Responsiveness to Thalidomide-Analog Drugs Defined by the Crystal Structure of the Human Cereblon:DDB1:Lenalidomide Complex
Authors: Chamberlain, P.P. / Wang, M. / Riley, M. / Delker, S. / Carmel, G. / Miller, K. / Lopez-Girona, A. / Pagarigan, B. / Leon, B. / Rychak, E. / Corral, L. / Lopez-Girona, A. / Ren, Y. / Wang, M. ...Authors: Chamberlain, P.P. / Wang, M. / Riley, M. / Delker, S. / Carmel, G. / Miller, K. / Lopez-Girona, A. / Pagarigan, B. / Leon, B. / Rychak, E. / Corral, L. / Lopez-Girona, A. / Ren, Y. / Wang, M. / Riley, M. / Delker, S. / Ito, T. / Hideki, A. / Mori, T. / Handa, H. / Hakoshima, T. / Daniel, T.O. / Miller, K. / Cathers, B.E. / Carmel, G. / Pagarigan, B. / Leon, B. / Rychak, E. / Corral, L. / Ren, Y.
History
DepositionJul 9, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 6, 2014Provider: repository / Type: Initial release
Revision 2.0Dec 27, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: atom_site_anisotrop / chem_comp_atom ...atom_site_anisotrop / chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / refine_hist
Item: _atom_site_anisotrop.pdbx_PDB_model_num / _atom_site_anisotrop.pdbx_label_asym_id ..._atom_site_anisotrop.pdbx_PDB_model_num / _atom_site_anisotrop.pdbx_label_asym_id / _atom_site_anisotrop.pdbx_label_atom_id / _atom_site_anisotrop.pdbx_label_comp_id / _atom_site_anisotrop.pdbx_label_seq_id / _citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein
Revision 2.1Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)172,0714
Polymers171,7472
Non-polymers3252
Water32418
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4320 Å2
ΔGint-25 kcal/mol
Surface area59790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.862, 129.117, 198.677
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Detailsbiological unit is the same as asym.

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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: 127879.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DDB1, XAP1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q16531
#2: Protein Protein cereblon


Mass: 43867.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CRBN, AD-006 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q96SW2
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-LVY / S-Lenalidomide


Mass: 259.261 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H13N3O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 18 / Source method: isolated from a natural source / Formula: H2O

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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: 2.68 Å3/Da / Density % sol: 54.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 100mM HEPES pH 7.5, 18% PEG 10K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jan 15, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3.01→50 Å / Num. obs: 37313 / % possible obs: 98.5 % / Redundancy: 6.1 % / Rmerge(I) obs: 0.181 / Χ2: 1.058 / Net I/av σ(I): 10.061 / Net I/σ(I): 5.9 / Num. measured all: 228575
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
3.01-3.125.80.72331841.0285.8
3.12-3.246.30.58437031.08299.9
3.24-3.396.30.39237311.08100
3.39-3.576.30.29437391.054100
3.57-3.796.30.2337681.045100
3.79-4.086.20.18737451.04599.9
4.08-4.56.20.14737951.034100
4.5-5.156.10.12137961.08899.9
5.15-6.486.10.13638351.08799.9
6.48-505.60.08240171.03699.5

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
HKL-3000data reduction
PDB_EXTRACT3.14data extraction
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: DDB1

Resolution: 3.01→50 Å / Cor.coef. Fo:Fc: 0.918 / Cor.coef. Fo:Fc free: 0.873 / SU B: 38.571 / SU ML: 0.328 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.465 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2706 1857 5 %RANDOM
Rwork0.2015 35396 --
obs0.2049 37253 99.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 79.43 Å2 / Biso mean: 30.294 Å2 / Biso min: 11.62 Å2
Baniso -1Baniso -2Baniso -3
1--1.52 Å20 Å20 Å2
2--1.67 Å20 Å2
3----0.16 Å2
Refinement stepCycle: final / Resolution: 3.01→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11043 0 20 18 11081
Biso mean--38.05 25.48 -
Num. residues----1431
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0211307
X-RAY DIFFRACTIONr_angle_refined_deg1.2111.9615349
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.38251410
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.81224.444477
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.871151876
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.1841553
X-RAY DIFFRACTIONr_chiral_restr0.0820.21786
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0218412
LS refinement shellResolution: 3.01→3.088 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 111 -
Rwork0.27 2223 -
all-2334 -
obs--92.95 %
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)
13.58141.04380.20933.2779-0.40013.21250.1427-0.36940.35310.414-0.1791-0.0495-0.480.52610.03630.1819-0.1725-0.02230.34010.00730.0512-0.295515.1173-7.6299
20.6744-0.086-0.12851.59280.40010.94170.01390.0822-0.0329-0.217-0.014-0.08570.06280.01730.00010.1202-0.01180.00690.11550.0450.0815-13.09043.8364-65.2819
31.1981-0.3355-0.16310.69110.00810.6488-0.026-0.02450.1280.06160.03970.0221-0.0573-0.0277-0.01370.1081-0.01710.03110.06760.01680.1493-21.449729.8526-47.2447
40.2447-0.85380.27454.0544-0.75721.5630.1740.0776-0.0597-0.1843-0.01330.20170.4191-0.0262-0.16070.31120.0353-0.06290.21680.01880.1573-31.494919.5893-66.7327
51.245-0.55520.87091.2852-0.87881.94470.0184-0.08270.04080.0163-0.1457-0.0825-0.063-0.00840.12730.21440.0164-0.01120.11390.0240.1062-36.929247.0136-87.0997
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A393 - 708
2X-RAY DIFFRACTION2A2 - 392
3X-RAY DIFFRACTION3A709 - 1147
4X-RAY DIFFRACTION4C187 - 256
5X-RAY DIFFRACTION5C48 - 186
6X-RAY DIFFRACTION5C257 - 428

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