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- PDB-5fqd: Structural basis of Lenalidomide induced CK1a degradation by the ... -

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Basic information

Entry
Database: PDB / ID: 5fqd
TitleStructural basis of Lenalidomide induced CK1a degradation by the crl4crbn ubiquitin ligase
Components
  • CASEIN KINASE I ISOFORM ALPHA
  • DNA DAMAGE-BINDING PROTEIN 1
  • PROTEIN CEREBLON
KeywordsLIGASE / DNA BINDING
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / Activation of SMO / intermediate filament cytoskeleton organization / negative regulation of NLRP3 inflammasome complex assembly / cellular response to nutrient / beta-catenin destruction complex / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / positive regulation by virus of viral protein levels in host cell ...negative regulation of monoatomic ion transmembrane transport / Activation of SMO / intermediate filament cytoskeleton organization / negative regulation of NLRP3 inflammasome complex assembly / cellular response to nutrient / beta-catenin destruction complex / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / positive regulation by virus of viral protein levels in host cell / spindle assembly involved in female meiosis / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / epigenetic programming in the zygotic pronuclei / UV-damage excision repair / Disassembly of the destruction complex and recruitment of AXIN to the membrane / biological process involved in interaction with symbiont / Maturation of nucleoprotein / 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 / positive regulation of Rho protein signal transduction / Golgi organization / 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 / positive regulation of TORC1 signaling / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / nucleotide-excision repair / Degradation of beta-catenin by the destruction complex / positive regulation of protein-containing complex assembly / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / negative regulation of canonical Wnt signaling pathway / Formation of Incision Complex in GG-NER / regulation of circadian rhythm / kinetochore / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / spindle / Wnt signaling pathway / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / damaged DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / transmembrane transporter binding / chromosome, telomeric region / cell surface receptor signaling pathway / protein phosphorylation / non-specific serine/threonine protein kinase / protein ubiquitination / protein kinase activity / viral protein processing / nuclear speck / ciliary basal body / cilium / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / apoptotic process / centrosome / DNA damage response / negative regulation of apoptotic process / protein-containing complex binding / nucleolus / perinuclear region of cytoplasm / signal transduction / protein-containing complex / extracellular space / DNA binding / extracellular exosome / nucleoplasm / ATP binding
Similarity search - Function
Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1480 / LON domain-like / Peptide methionine sulfoxide reductase. / DNA polymerase; domain 1 - #910 / Metal Binding Protein, Guanine Nucleotide Exchange Factor; Chain A / Archaeosine Trna-guanine Transglycosylase; Chain: A, domain 4 / Yippee/Mis18/Cereblon / Yippee zinc-binding/DNA-binding /Mis18, centromere assembly / : / CULT domain ...Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #1480 / LON domain-like / Peptide methionine sulfoxide reductase. / DNA polymerase; domain 1 - #910 / Metal Binding Protein, Guanine Nucleotide Exchange Factor; Chain A / Archaeosine Trna-guanine Transglycosylase; Chain: A, domain 4 / 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 / YVTN repeat-like/Quinoprotein amine dehydrogenase / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Beta Complex / 7 Propeller / Methylamine Dehydrogenase; Chain H / DNA polymerase; domain 1 / Roll / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Up-down Bundle / 2-Layer Sandwich / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
S-Lenalidomide / Casein kinase I isoform alpha / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 Å
AuthorsPetzold, G. / Fischer, E.S. / Thoma, N.H.
CitationJournal: Nature / Year: 2016
Title: Structural Basis of Lenalidomide-Induced Ck1Alpha Degradation by the Crl4(Crbn) Ubiquitin Ligase.
Authors: Petzold, G. / Fischer, E.S. / Thoma, N.H.
History
DepositionDec 9, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 24, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2016Group: Database references
Revision 1.2Apr 13, 2016Group: Database references
Revision 1.3Apr 3, 2019Group: Data collection / Other / Source and taxonomy
Category: entity_src_gen / pdbx_database_proc / pdbx_database_status
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_database_status.recvd_author_approval
Revision 1.4Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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: CASEIN KINASE I ISOFORM ALPHA
D: DNA DAMAGE-BINDING PROTEIN 1
E: PROTEIN CEREBLON
F: CASEIN KINASE I ISOFORM ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)368,75310
Polymers368,1046
Non-polymers6494
Water5,495305
1
A: DNA DAMAGE-BINDING PROTEIN 1
B: PROTEIN CEREBLON
C: CASEIN KINASE I ISOFORM ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)184,3775
Polymers184,0523
Non-polymers3252
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
D: DNA DAMAGE-BINDING PROTEIN 1
E: PROTEIN CEREBLON
F: CASEIN KINASE I ISOFORM ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)184,3775
Polymers184,0523
Non-polymers3252
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)87.970, 109.930, 112.400
Angle α, β, γ (deg.)106.02, 93.19, 101.63
Int Tables number1
Space group name H-MP1

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Components

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Protein , 3 types, 6 molecules ADBECF

#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.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): High Five / Production host: TRICHOPLUSIA NI (cabbage looper) / References: UniProt: Q16531, ubiquitin-protein ligase
#2: Protein PROTEIN CEREBLON


Mass: 48976.117 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): High Five / Production host: TRICHOPLUSIA NI (cabbage looper) / References: UniProt: Q96SW2
#3: Protein CASEIN KINASE I ISOFORM ALPHA / CKI-ALPHA / CK1 / CASEINE KINASE 1A


Mass: 39302.238 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): High Five / Production host: TRICHOPLUSIA NI (cabbage looper) / References: UniProt: P48729

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Non-polymers , 3 types, 309 molecules

#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-LVY / S-Lenalidomide


Mass: 259.261 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H13N3O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 305 / 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: 2.76 Å3/Da / Density % sol: 55 % / Description: NONE
Crystal growDetails: 70 MM TRIS PH 7.0 140 MM MGCL2 7% W/V PEG 8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.28161
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 20, 2015 / Details: MIRRORS
RadiationMonochromator: SI CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.28161 Å / Relative weight: 1
ReflectionResolution: 2.45→65.3 Å / Num. obs: 140745 / % possible obs: 97.3 % / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Biso Wilson estimate: 75.89 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 8.7
Reflection shellResolution: 2.45→2.58 Å / Redundancy: 3.7 % / Rmerge(I) obs: 1.5 / Mean I/σ(I) obs: 0.8 / % possible all: 96.5

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3EI3

3ei3


Resolution: 2.45→65.3 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.928 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.317 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.289 / SU Rfree Blow DPI: 0.203 / SU Rfree Cruickshank DPI: 0.212
RfactorNum. reflection% reflectionSelection details
Rfree0.21 6991 4.97 %RANDOM
Rwork0.181 ---
obs0.182 140745 97.3 %-
Displacement parametersBiso mean: 96.76 Å2
Baniso -1Baniso -2Baniso -3
1--12.3703 Å223.6353 Å24.4985 Å2
2---4.6699 Å2-3.9554 Å2
3---17.0401 Å2
Refine analyzeLuzzati coordinate error obs: 0.35 Å
Refinement stepCycle: LAST / Resolution: 2.45→65.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms23199 0 40 305 23544
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0123716HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1832089HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d8332SINUSOIDAL4
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes608HARMONIC2
X-RAY DIFFRACTIONt_gen_planes3389HARMONIC5
X-RAY DIFFRACTIONt_it23716HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion17
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion3087SEMIHARMONIC5
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_contact25816SEMIHARMONIC4
LS refinement shellResolution: 2.45→2.51 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.239 520 5.04 %
Rwork0.222 9792 -
all0.223 10312 -
obs--96.86 %
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)
11.44990.7044-1.30061.8364-1.61744.2725-0.0944-0.3308-0.208-0.2648-0.30190.01580.61920.2170.3963-0.57760.05730.086-0.5620.0508-0.69734.5617109.7082-41.3296
20.5593-0.04090.86090.91520.56322.4749-0.07570.21320.0873-0.06180.1156-0.0879-0.01960.2482-0.0398-0.228-0.04130.0352-0.22420.0592-0.280541.3621122.9394-2.8525
31.07620.3243-0.12852.3735-0.0321.3111-0.0941-0.3122-0.0180.45990.13780.33510.0053-0.0256-0.0437-0.25460.13640.0308-0.23050.0601-0.23148.834161.701129.8175
41.93790.5823-0.22511.3195-0.4571.4605-0.21180.19170.3081-0.1640.14240.01720.02410.05620.0694-0.4109-0.0193-0.0996-0.41080.0329-0.29697.616271.8864-3.9657
50.11740.22111.35341.90943.34734.7258-0.25770.5966-0.0341-0.40110.6754-0.2571-0.34251.2876-0.4177-0.1905-0.44330.06450.2986-0.127-0.50210.997150.5185-38.9549
62.62490.5451-1.63551.3108-0.21684.0748-0.1523-0.0716-0.001-0.05980.08990.0079-0.04250.43260.0624-0.24780.05890.0296-0.32960.0096-0.4283-10.209422.0393-76.5974
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }
3X-RAY DIFFRACTION3{ C|* }
4X-RAY DIFFRACTION4{ D|* }
5X-RAY DIFFRACTION5{ E|* }
6X-RAY DIFFRACTION6{ F|* }

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