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- PDB-6uml: Structural Basis for Thalidomide Teratogenicity Revealed by the C... -

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Basic information

Entry
Database: PDB / ID: 6uml
TitleStructural Basis for Thalidomide Teratogenicity Revealed by the Cereblon-DDB1-SALL4-Pomalidomide Complex
Components
  • DNA damage-binding protein 1
  • Protein cereblon
  • Sal-like protein 4
KeywordsLIGASE / CELMoD / cereblon-CRL4 / ubiquitin ligase / C2H2 zinc finger
Function / homology
Function and homology information


POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation / negative regulation of monoatomic ion transmembrane transport / Transcriptional regulation of pluripotent stem cells / 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 / embryonic limb morphogenesis / biological process involved in interaction with symbiont / inner cell mass cell proliferation ...POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation / negative regulation of monoatomic ion transmembrane transport / Transcriptional regulation of pluripotent stem cells / 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 / embryonic limb morphogenesis / biological process involved in interaction with symbiont / inner cell mass cell proliferation / regulation of mitotic cell cycle phase transition / ventricular septum development / 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 / somatic stem cell population maintenance / 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 / heterochromatin / positive regulation of gluconeogenesis / Regulation of PTEN gene transcription / nucleotide-excision repair / neural tube closure / 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 / DNA-binding transcription factor activity, RNA polymerase II-specific / chromosome, telomeric region / protein ubiquitination / DNA repair / intracellular membrane-bounded organelle / 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 / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / protein-containing complex / extracellular space / DNA binding / extracellular exosome / zinc ion binding / nucleoplasm / metal ion binding / nucleus / membrane / cytoplasm / cytosol
Similarity search - Function
: / DNA polymerase; domain 1 - #910 / 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 ...: / DNA polymerase; domain 1 - #910 / 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. / YVTN repeat-like/Quinoprotein amine dehydrogenase / Zinc finger C2H2-type / 7 Propeller / Methylamine Dehydrogenase; Chain H / DNA polymerase; domain 1 / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Orthogonal Bundle / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
S-Pomalidomide / DNA damage-binding protein 1 / Protein cereblon / Sal-like protein 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.58 Å
AuthorsClayton, T.L. / Matyskiela, M.E. / Pagarigan, B.E. / Tran, E.T. / Chamberlain, P.P.
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2020
Title: Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex.
Authors: Matyskiela, M.E. / Clayton, T. / Zheng, X. / Mayne, C. / Tran, E. / Carpenter, A. / Pagarigan, B. / McDonald, J. / Rolfe, M. / Hamann, L.G. / Lu, G. / Chamberlain, P.P.
History
DepositionOct 9, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2020Group: 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
Revision 1.2Oct 11, 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
Revision 1.3Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: DNA damage-binding protein 1
C: Protein cereblon
E: Sal-like protein 4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)177,3596
Polymers176,9553
Non-polymers4043
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)77.409, 127.725, 110.174
Angle α, β, γ (deg.)90.000, 109.694, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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.: 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: 46596.566 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: Protein/peptide Sal-like protein 4 / Zinc finger protein 797 / Zinc finger protein SALL4


Mass: 3260.777 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SALL4, ZNF797 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UJQ4
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / 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
Has ligand of interestY
Has protein modificationY

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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: 2.9 Å3/Da / Density % sol: 57.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 10% PEG MME 500, 8% PEG 20K, 210mM calcium acetate, 100mM tris pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 3.58→38.7 Å / Num. obs: 23629 / % possible obs: 98.42 % / Redundancy: 3.4 % / Biso Wilson estimate: 79.26 Å2 / CC1/2: 0.964 / Rmerge(I) obs: 0.1637 / Rpim(I) all: 0.1042 / Rrim(I) all: 0.1948 / Net I/σ(I): 5.04
Reflection shellResolution: 3.58→3.64 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.5699 / Num. unique obs: 2336 / CC1/2: 0.734 / Rpim(I) all: 0.3551 / Rrim(I) all: 0.6734 / % possible all: 98.11

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
xia2data reduction
DIALSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4TZ4

4tz4


Resolution: 3.58→38.7 Å / SU ML: 0.5122 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 29.413
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2671 1092 4.63 %
Rwork0.2038 22484 -
obs0.2066 23576 98.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 85.16 Å2
Refinement stepCycle: LAST / Resolution: 3.58→38.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11082 0 22 0 11104
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004411319
X-RAY DIFFRACTIONf_angle_d0.679115386
X-RAY DIFFRACTIONf_chiral_restr0.0461806
X-RAY DIFFRACTIONf_plane_restr0.00561959
X-RAY DIFFRACTIONf_dihedral_angle_d6.33476736
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.58-3.740.35141380.28122775X-RAY DIFFRACTION98.15
3.74-3.940.34051240.2472851X-RAY DIFFRACTION99.33
3.94-4.180.29531650.21592763X-RAY DIFFRACTION99.39
4.18-4.510.21951390.17642806X-RAY DIFFRACTION98.4
4.51-4.960.22861170.16412802X-RAY DIFFRACTION97.85
4.96-5.670.26021330.18232859X-RAY DIFFRACTION99.63
5.67-7.140.26131430.22872803X-RAY DIFFRACTION97.81
7.14-38.70.25441330.19662825X-RAY DIFFRACTION97.24
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)
11.425305329651.21763860480.2463815815973.459808664670.2419305034052.09047395167-0.02454022316130.446357033972-0.373170775212-0.591840849049-0.0576017276235-0.3210328457190.3403835269810.07378158893510.07486097415850.6890075394090.1425095067540.1534607580780.677219160499-0.1397016325860.67782383879942.7778254148-23.6904678344-71.5911674686
21.795088504881.073032220320.4468757481612.690864527970.3904344294882.936574790920.12637013140.184417997658-0.01310675362270.187426315655-0.0304961840381-0.141962519434-0.1121188178670.421269406314-0.06031326844350.4598001354850.0462696787629-0.1025351850370.544684538834-0.03080415668280.45226233482558.0234312791-11.1076800603-9.76331139934
32.38891684936-0.0319232551968-0.3135540772732.29761198871-0.3458784506241.35026516817-0.06806968539510.08026662959860.1711245411440.2628062804670.03733575908210.0735157403983-0.205790354042-0.01068001663510.03698081996010.53583062327-0.006411676703-0.01839655383420.4307602302530.05115961480990.4307115995827.01449119353.1075821513-48.9387360834
46.305739939730.2758481020240.8215470850267.67064210547-1.83566461666.07774883787-0.2706040290850.7345968529041.094551073710.0596629550338-0.536353656029-1.5494519552-1.207918043440.7939857557090.8342054960120.848876627133-0.0848449113696-0.1374909693730.7675899246450.2973684931260.90370050754428.717422832724.248847956-93.8306386015
53.27389145652-2.083410387521.842555511776.94447702429-2.762736834624.849290076050.306775307891-0.0342986737396-0.162534638577-0.9535708318650.1609534000080.3858879317540.244078965502-0.541875102295-0.4790087466850.625806135924-0.0220173607741-0.06228826442320.5760930154020.06204565549990.61907393642619.6424147332.97006317683-72.8584777878
66.95999495068-1.47716012596-1.378749945114.671959251421.871573384841.60028915882-0.263045390989-0.2662114209580.0859235526522-0.2470826846720.1110389139810.196834742602-0.0258012542250.1029365333580.1177825587650.7616576450150.0469645267823-0.156430512210.4581645962560.1011706347350.4241130456952.8046082942222.7988329205-88.3752515934
71.677678201642.87395757691-2.119992243857.41679499394-3.200020105662.788203656050.7694389414910.8190299102341.4007454726-0.5351273144170.5021742912420.533472388743-0.184971018223-0.592388851585-1.090224655421.25075272995-0.0908781071490.08641413400420.8600388051740.1684869892841.02166405063.826178298638.7750388654-98.5063025955
83.279402197441.34801941157-3.096890857548.153283237222.896973130915.212798439081.185606299050.1283534986460.9498026754740.3063236181490.946244502733-0.459359887406-1.169478634440.267147052729-1.955782155940.959168309773-0.2582223878110.216302666011.01867743613-0.003288974613550.851178408856.3937059950643.2725944457-91.6322281241
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 355 )
2X-RAY DIFFRACTION2chain 'A' and (resid 394 through 672 )
3X-RAY DIFFRACTION3chain 'A' and (resid 713 through 1081 )
4X-RAY DIFFRACTION4chain 'C' and (resid 60 through 186)
5X-RAY DIFFRACTION5chain 'C' and (resid 200 through 317 )
6X-RAY DIFFRACTION6chain 'C' and (resid 319 through 427)
7X-RAY DIFFRACTION7chain 'E' and (resid 408 through 421 )
8X-RAY DIFFRACTION8chain 'E' and (resid 422 through 432 )

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