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- PDB-8rqc: Crystal structure of CRBN-midi in complex with mezigdomide and IK... -

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Basic information

Entry
Database: PDB / ID: 8rqc
TitleCrystal structure of CRBN-midi in complex with mezigdomide and IKZF1 ZF2
Components
  • DNA-binding protein Ikaros
  • Protein cereblon
KeywordsLIGASE / E3 ligase / PROTAC / TPD / molecular glue / targeted protein degradation
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / lymphocyte differentiation / NOTCH3 Intracellular Domain Regulates Transcription / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / mesoderm development / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / pericentric heterochromatin / erythrocyte differentiation ...negative regulation of monoatomic ion transmembrane transport / lymphocyte differentiation / NOTCH3 Intracellular Domain Regulates Transcription / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / mesoderm development / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / pericentric heterochromatin / erythrocyte differentiation / positive regulation of protein-containing complex assembly / chromatin organization / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / Potential therapeutics for SARS / protein ubiquitination / DNA-binding transcription factor activity / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein domain specific binding / negative regulation of DNA-templated transcription / regulation of transcription by RNA polymerase II / perinuclear region of cytoplasm / protein-containing complex / DNA binding / nucleoplasm / identical protein binding / membrane / nucleus / metal ion binding / cytosol / cytoplasm
Similarity search - Function
: / 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) ...: / 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) / 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. / Zinc finger C2H2-type
Similarity search - Domain/homology
Mezigdomide / DNA-binding protein Ikaros / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsFurihata, H. / Kroupova, A. / Zollman, D. / Ciulli, A.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Nat Commun / Year: 2024
Title: Design of a Cereblon construct for crystallographic and biophysical studies of protein degraders.
Authors: Kroupova, A. / Spiteri, V.A. / Rutter, Z.J. / Furihata, H. / Darren, D. / Ramachandran, S. / Chakraborti, S. / Haubrich, K. / Pethe, J. / Gonzales, D. / Wijaya, A.J. / Rodriguez-Rios, M. / ...Authors: Kroupova, A. / Spiteri, V.A. / Rutter, Z.J. / Furihata, H. / Darren, D. / Ramachandran, S. / Chakraborti, S. / Haubrich, K. / Pethe, J. / Gonzales, D. / Wijaya, A.J. / Rodriguez-Rios, M. / Sturbaut, M. / Lynch, D.M. / Farnaby, W. / Nakasone, M.A. / Zollman, D. / Ciulli, A.
History
DepositionJan 17, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein cereblon
B: DNA-binding protein Ikaros
D: Protein cereblon
E: DNA-binding protein Ikaros
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,39410
Polymers82,9974
Non-polymers1,3976
Water3,225179
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.585, 142.842, 56.693
Angle α, β, γ (deg.)90.000, 112.341, 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
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 64 through 70 or (resid 71...
d_2ens_1(chain "D" and (resid 64 through 67 or (resid 70...
d_1ens_2(chain "B" and (resid 144 through 155 or (resid 156...
d_2ens_2(chain "E" and (resid 144 through 164 or (resid 165...
d_1ens_3chain "C"
d_2ens_3chain "F"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1METMETVALVALAA64 - 12825 - 89
d_12ens_1GLUGLULYSLYSAA132 - 31793 - 220
d_13ens_1THRTHRTHRTHRAA319 - 425222 - 328
d_21ens_1METMETPHEPHEDC64 - 6725 - 28
d_22ens_1ARGARGVALVALDC70 - 12831 - 89
d_23ens_1GLUGLULYSLYSDC132 - 31793 - 220
d_24ens_1THRTHRTHRTHRDC319 - 425222 - 328
d_11ens_2PROPROGLUGLUBB144 - 1706 - 32
d_21ens_2PROPROGLUGLUED144 - 1706 - 32
d_11ens_3QFCQFCQFCQFCAF602
d_21ens_3QFCQFCQFCQFCDI602

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(0.999938374876, 0.0074499040083, 0.0082307581618), (-0.00870572470389, 0.0661441204367, 0.997772101078), (0.00688889011604, -0.997782267963, 0.0662049011105)4.05952435032, 27.1920133249, 10.0610537214
2given(0.996011917047, -0.0886125562329, -0.0103959596902), (0.0113944885167, 0.010770082646, 0.999877077921), (-0.0884896984482, -0.996007941835, 0.0117368254175)2.39352961466, 26.6777646986, 9.28221081231
3given(0.996651582245, -0.0706976093748, 0.0410788465999), (-0.0374941749046, 0.0513057497306, 0.997978911046), (-0.0726623042403, -0.9961774782, 0.048483208116)3.00178193825, 26.9990169492, 10.1637717186

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Components

#1: Protein Protein cereblon


Mass: 37478.805 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: Escherichia coli (E. coli) / References: UniProt: Q96SW2
#2: Protein/peptide DNA-binding protein Ikaros / Ikaros family zinc finger protein 1 / Lymphoid transcription factor LyF-1


Mass: 4019.614 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IKZF1, IK1, IKAROS, LYF1, ZNFN1A1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13422
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-QFC / Mezigdomide


Mass: 567.610 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C32H30FN5O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 179 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.48 Å3/Da / Density % sol: 50.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.2 M ammonium sulphate, 25% (w/v) PEG 3350, and 0.1 M HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.957 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Sep 23, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.957 Å / Relative weight: 1
ReflectionResolution: 2.15→52.44 Å / Num. obs: 42776 / % possible obs: 97.56 % / Redundancy: 7.1 % / Biso Wilson estimate: 50.06 Å2 / CC1/2: 0.996 / CC star: 0.999 / Rmerge(I) obs: 0.2004 / Rpim(I) all: 0.08074 / Rrim(I) all: 0.2162 / Net I/σ(I): 6.12
Reflection shellResolution: 2.15→2.227 Å / Redundancy: 7.2 % / Rmerge(I) obs: 3.696 / Mean I/σ(I) obs: 0.32 / Num. unique obs: 4266 / CC1/2: 0.343 / CC star: 0.715 / Rpim(I) all: 1.477 / Rrim(I) all: 3.984 / % possible all: 80.1

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
xia2data scaling
PHASERphasing
Cootmodel building
xia2data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.15→52.44 Å / SU ML: 0.4658 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 40.4494
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2859 1974 4.73 %
Rwork0.2607 39801 -
obs0.2619 41775 97.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 62.45 Å2
Refinement stepCycle: LAST / Resolution: 2.15→52.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5033 0 88 179 5300
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01035237
X-RAY DIFFRACTIONf_angle_d1.46127135
X-RAY DIFFRACTIONf_chiral_restr0.0881805
X-RAY DIFFRACTIONf_plane_restr0.0073919
X-RAY DIFFRACTIONf_dihedral_angle_d17.03351849
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS1.30461395183
ens_2d_2BBX-RAY DIFFRACTIONTorsion NCS1.55217381539
ens_3d_2FAX-RAY DIFFRACTIONTorsion NCS1.14823804695
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.20.4419920.48042069X-RAY DIFFRACTION71.2
2.2-2.260.47211410.46232874X-RAY DIFFRACTION97.67
2.26-2.330.43191440.44362845X-RAY DIFFRACTION98.78
2.33-2.40.44021410.41422885X-RAY DIFFRACTION99.47
2.4-2.490.36421700.37932860X-RAY DIFFRACTION99.57
2.49-2.590.41011560.34462920X-RAY DIFFRACTION99.45
2.59-2.710.35031300.32152910X-RAY DIFFRACTION99.48
2.71-2.850.32521360.28892899X-RAY DIFFRACTION99.57
2.85-3.030.32841360.28572912X-RAY DIFFRACTION99.74
3.03-3.260.29681380.27072911X-RAY DIFFRACTION99.74
3.26-3.590.27651290.24432934X-RAY DIFFRACTION99.74
3.59-4.110.2741560.21442915X-RAY DIFFRACTION100
4.11-5.180.20961650.19642907X-RAY DIFFRACTION99.93
5.18-52.440.24911400.23022960X-RAY DIFFRACTION99.68

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