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- PDB-6xk9: Cereblon in complex with DDB1, CC-90009, and GSPT1 -

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Basic information

Entry
Database: PDB / ID: 6xk9
TitleCereblon in complex with DDB1, CC-90009, and GSPT1
Components
  • DNA damage-binding protein 1
  • Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
  • Protein cereblon
KeywordsLIGASE / DDB1 / molecular glue / degradation / CC-90009 / Acute Myeloid Leukemia
Function / homology
Function and homology information


translation release factor complex / negative regulation of monoatomic ion transmembrane transport / regulation of translational termination / translation release factor activity / protein methylation / 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 ...translation release factor complex / negative regulation of monoatomic ion transmembrane transport / regulation of translational termination / translation release factor activity / protein methylation / 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 / nuclear-transcribed mRNA catabolic process, nonsense-mediated decay / 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 / Eukaryotic Translation Termination / positive regulation of Wnt signaling pathway / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / viral release from host cell / ectopic germ cell programmed cell death / positive regulation of viral genome replication / negative regulation of protein-containing complex assembly / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / translational termination / positive regulation of gluconeogenesis / cytosolic ribosome / proteasomal protein catabolic process / Recognition of DNA damage by PCNA-containing replication complex / nucleotide-excision repair / positive regulation of protein-containing complex assembly / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / DNA Damage Recognition in GG-NER / G1/S transition of mitotic cell cycle / 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 / Regulation of expression of SLITs and ROBOs / 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 / translation / DNA repair / GTPase activity / apoptotic process / DNA damage response / protein-containing complex binding / GTP binding / nucleolus / negative regulation of apoptotic process / perinuclear region of cytoplasm / protein-containing complex / DNA binding / extracellular space / RNA binding / 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) / Translation elongation factor EFTu/EF1A, C-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) / Translation elongation factor EFTu/EF1A, C-terminal / Elongation factor Tu C-terminal domain / 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 / Translation elongation factor EF1A/initiation factor IF2gamma, C-terminal / PUA-like superfamily / Tr-type G domain, conserved site / Translational (tr)-type guanine nucleotide-binding (G) domain signature. / Translation elongation factor EFTu-like, domain 2 / Elongation factor Tu domain 2 / Translational (tr)-type GTP-binding domain / Elongation factor Tu GTP binding domain / Translational (tr)-type guanine nucleotide-binding (G) domain profile. / Translation protein, beta-barrel domain superfamily / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-V4M / Eukaryotic peptide chain release factor GTP-binding subunit ERF3A / DNA damage-binding protein 1 / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.64 Å
AuthorsClayton, T.L. / Tran, E.T. / Zhu, J. / Pagarigan, B.E. / Matyskiela, M.E. / Chamberlain, P.P.
CitationJournal: Blood / Year: 2021
Title: CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells.
Authors: Surka, C. / Jin, L. / Mbong, N. / Lu, C.C. / Jang, I.S. / Rychak, E. / Mendy, D. / Clayton, T. / Tindall, E. / Hsu, C. / Fontanillo, C. / Tran, E. / Contreras, A. / Ng, S.W.K. / Matyskiela, ...Authors: Surka, C. / Jin, L. / Mbong, N. / Lu, C.C. / Jang, I.S. / Rychak, E. / Mendy, D. / Clayton, T. / Tindall, E. / Hsu, C. / Fontanillo, C. / Tran, E. / Contreras, A. / Ng, S.W.K. / Matyskiela, M. / Wang, K. / Chamberlain, P. / Cathers, B. / Carmichael, J. / Hansen, J. / Wang, J.C.Y. / Minden, M.D. / Fan, J. / Pierce, D.W. / Pourdehnad, M. / Rolfe, M. / Lopez-Girona, A. / Dick, J.E. / Lu, G.
History
DepositionJun 25, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation.year / _citation_author.name
Revision 1.2Oct 18, 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
X: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
Y: DNA damage-binding protein 1
Z: Protein cereblon
A: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
B: DNA damage-binding protein 1
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)392,43410
Polymers391,3806
Non-polymers1,0554
Water0
1
X: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
Y: DNA damage-binding protein 1
Z: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,2175
Polymers195,6903
Non-polymers5272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6010 Å2
ΔGint-38 kcal/mol
Surface area69350 Å2
MethodPISA
2
A: Eukaryotic peptide chain release factor GTP-binding subunit ERF3A
B: DNA damage-binding protein 1
C: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)196,2175
Polymers195,6903
Non-polymers5272
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5780 Å2
ΔGint-38 kcal/mol
Surface area68650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)157.616, 112.041, 176.582
Angle α, β, γ (deg.)90.000, 95.791, 90.000
Int Tables number3
Space group name H-MP121
Space group name HallP2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
12
22
13
23

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
111GLYGLYLEULEU(chain 'A' and (resid 437 through 469 or (resid 470...AD437 - 6313 - 197
221GLYGLYLEULEU(chain 'X' and (resid 437 through 471 or (resid 472...XA437 - 6313 - 197
132SERSERTHRTHR(chain 'B' and (resid 2 through 345 or (resid 346...BE2 - 452 - 45
142LEULEULYSLYS(chain 'B' and (resid 2 through 345 or (resid 346...BE49 - 9249 - 92
152ILEILEGLUGLU(chain 'B' and (resid 2 through 345 or (resid 346...BE98 - 28698 - 286
162THRTHRVALVAL(chain 'B' and (resid 2 through 345 or (resid 346...BE296 - 365296 - 365
172GLNGLNASPASP(chain 'B' and (resid 2 through 345 or (resid 346...BE370 - 416370 - 416
182GLUGLUPROPRO(chain 'B' and (resid 2 through 345 or (resid 346...BE420 - 545420 - 545
192ASNASNTYRTYR(chain 'B' and (resid 2 through 345 or (resid 346...BE550 - 660550 - 660
1102ASNASNGLNGLN(chain 'B' and (resid 2 through 345 or (resid 346...BE663 - 743663 - 743
1112THRTHRLYSLYS(chain 'B' and (resid 2 through 345 or (resid 346...BE750 - 769750 - 769
1122GLUGLULYSLYS(chain 'B' and (resid 2 through 345 or (resid 346...BE784 - 979784 - 979
1132GLUGLUMETMET(chain 'B' and (resid 2 through 345 or (resid 346...BE987 - 1014987 - 1014
1142PROPROASPASP(chain 'B' and (resid 2 through 345 or (resid 346...BE1023 - 11161023 - 1116
1152LYSLYSILEILE(chain 'B' and (resid 2 through 345 or (resid 346...BE1121 - 11391121 - 1139
2162SERSERTHRTHR(chain 'Y' and (resid 2 through 94 or resid 98...YB2 - 452 - 45
2172LEULEULYSLYS(chain 'Y' and (resid 2 through 94 or resid 98...YB49 - 9249 - 92
2182ILEILEGLUGLU(chain 'Y' and (resid 2 through 94 or resid 98...YB98 - 28698 - 286
2192THRTHRVALVAL(chain 'Y' and (resid 2 through 94 or resid 98...YB296 - 365296 - 365
2202GLNGLNASPASP(chain 'Y' and (resid 2 through 94 or resid 98...YB370 - 416370 - 416
2222GLUGLUPROPRO(chain 'Y' and (resid 2 through 94 or resid 98...YB420 - 545420 - 545
2232ASNASNTYRTYR(chain 'Y' and (resid 2 through 94 or resid 98...YB550 - 660550 - 660
2242ASNASNGLNGLN(chain 'Y' and (resid 2 through 94 or resid 98...YB663 - 743663 - 743
2252THRTHRLYSLYS(chain 'Y' and (resid 2 through 94 or resid 98...YB750 - 769750 - 769
2262GLUGLULYSLYS(chain 'Y' and (resid 2 through 94 or resid 98...YB784 - 979784 - 979
2272GLUGLUMETMET(chain 'Y' and (resid 2 through 94 or resid 98...YB987 - 1014987 - 1014
2282PROPROASPASP(chain 'Y' and (resid 2 through 94 or resid 98...YB1023 - 11161023 - 1116
2292LYSLYSILEILE(chain 'Y' and (resid 2 through 94 or resid 98...YB1121 - 11391121 - 1139
1303ILEILEPROPRO(chain 'C' and (resid 47 through 64 or (resid 65...CF47 - 21211 - 176
1313SERSERPROPRO(chain 'C' and (resid 47 through 64 or (resid 65...CF220 - 427184 - 391
1323VALVALCYSCYS(chain 'C' and (resid 47 through 64 or (resid 65...CF438 - 441402 - 405
1333ZNZNZNZN(chain 'C' and (resid 47 through 64 or (resid 65...CJ502
2343ILEILEPROPRO(chain 'Z' and ((resid 47 and (name N or name...ZC47 - 21211 - 176
2353SERSERPROPRO(chain 'Z' and ((resid 47 and (name N or name...ZC220 - 427184 - 391
2363VALVALCYSCYS(chain 'Z' and ((resid 47 and (name N or name...ZC438 - 441402 - 405
2373V4MV4MV4MV4M(chain 'Z' and ((resid 47 and (name N or name...ZG501

NCS ensembles :
ID
1
2
3

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Components

#1: Protein Eukaryotic peptide chain release factor GTP-binding subunit ERF3A / eRF3a / G1 to S phase transition protein 1 homolog


Mass: 21995.799 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GSPT1, ERF3A / Production host: Escherichia coli (E. coli) / References: UniProt: P15170
#2: Protein DNA damage-binding protein 1 / DDB p127 subunit / DNA damage-binding protein a / Damage-specific DNA-binding protein 1 / HBV X- ...DDB p127 subunit / DNA damage-binding protein a / Damage-specific DNA-binding protein 1 / HBV X-associated protein 1 / UV-damaged DNA-binding factor / UV-damaged DNA-binding protein 1 / XPE-binding factor / Xeroderma pigmentosum group E-complementing protein


Mass: 127097.469 Da / Num. of mol.: 2
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
#3: Protein Protein cereblon


Mass: 46596.566 Da / Num. of mol.: 2
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
#4: Chemical ChemComp-V4M / 2-(4-chlorophenyl)-N-({2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)-2,2-difluoroacetamide


Mass: 461.846 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H18ClF2N3O4 / 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

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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: 3.96 Å3/Da / Density % sol: 68.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG 3350, 100mM Tris-HCl (pH 7.5), 300mM sodium citrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 9, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 3.64→74.45 Å / Num. obs: 68917 / % possible obs: 99.82 % / Redundancy: 3.3 % / Biso Wilson estimate: 86.75 Å2 / CC1/2: 0.992 / CC star: 0.998 / Rmerge(I) obs: 0.1184 / Rpim(I) all: 0.07746 / Rrim(I) all: 0.1419 / Net I/σ(I): 4.49
Reflection shellResolution: 3.64→3.77 Å / Rmerge(I) obs: 0.4706 / Mean I/σ(I) obs: 2.33 / Num. unique obs: 6809 / CC1/2: 0.696 / Rpim(I) all: 0.3084 / Rrim(I) all: 0.5644

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
xia2data reduction
DIALSdata scaling
PHENIX1.17.1_3660phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5hxb

5hxb


Resolution: 3.64→74.45 Å / SU ML: 0.4154 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.6955
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2455 3355 4.87 %
Rwork0.2079 65527 -
obs0.2097 68882 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 93.1 Å2
Refinement stepCycle: LAST / Resolution: 3.64→74.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms25417 0 66 0 25483
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002625975
X-RAY DIFFRACTIONf_angle_d0.67335323
X-RAY DIFFRACTIONf_chiral_restr0.04714155
X-RAY DIFFRACTIONf_plane_restr0.00394517
X-RAY DIFFRACTIONf_dihedral_angle_d14.54383551
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.64-3.690.36651140.32672682X-RAY DIFFRACTION99.22
3.69-3.750.28381390.27892753X-RAY DIFFRACTION100
3.75-3.810.3011320.26682695X-RAY DIFFRACTION99.93
3.81-3.870.35211490.28322734X-RAY DIFFRACTION99.76
3.87-3.930.35091600.28322650X-RAY DIFFRACTION99.72
3.93-4.010.34031420.27542755X-RAY DIFFRACTION99.83
4.01-4.080.30481400.24452680X-RAY DIFFRACTION99.96
4.08-4.170.27841270.22482729X-RAY DIFFRACTION99.93
4.17-4.260.24981460.21952716X-RAY DIFFRACTION99.97
4.26-4.360.2471350.20822708X-RAY DIFFRACTION99.93
4.36-4.470.25761380.19332751X-RAY DIFFRACTION99.93
4.47-4.590.23591280.18882717X-RAY DIFFRACTION99.96
4.59-4.720.20031400.1822734X-RAY DIFFRACTION100
4.72-4.870.21321450.17382722X-RAY DIFFRACTION99.97
4.87-5.050.19831500.18222699X-RAY DIFFRACTION99.96
5.05-5.250.25711310.18542741X-RAY DIFFRACTION99.72
5.25-5.490.22751380.20012733X-RAY DIFFRACTION99.76
5.49-5.780.27741540.20842712X-RAY DIFFRACTION100
5.78-6.140.23181510.21482722X-RAY DIFFRACTION100
6.14-6.610.25991290.20552790X-RAY DIFFRACTION100
6.61-7.280.24171260.20542743X-RAY DIFFRACTION99.9
7.28-8.330.20561410.19092771X-RAY DIFFRACTION99.83
8.33-10.490.17861460.14662773X-RAY DIFFRACTION99.9
10.5-74.450.21381540.19262817X-RAY DIFFRACTION99.07

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