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- PDB-9cuo: Crystal structure of CRBN with compound 3 -

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Basic information

Entry
Database: PDB / ID: 9cuo
TitleCrystal structure of CRBN with compound 3
ComponentsProtein cereblon
KeywordsLIGASE / CRBN / E3 / protein degradation
Function / homology
Function and homology information


negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / positive regulation of protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / Potential therapeutics for SARS / protein ubiquitination ...negative regulation of monoatomic ion transmembrane transport / Cul4A-RING E3 ubiquitin ligase complex / locomotory exploration behavior / positive regulation of Wnt signaling pathway / negative regulation of protein-containing complex assembly / positive regulation of protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / Potential therapeutics for SARS / protein ubiquitination / perinuclear region of cytoplasm / 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) / PUA-like superfamily
Similarity search - Domain/homology
: / Protein cereblon
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsZheng, X. / Ji, N. / Campbell, V. / Slavin, A. / Zhu, X. / Chen, D. / Rong, H. / Enerson, B. / Mayo, M. / Sharma, K. ...Zheng, X. / Ji, N. / Campbell, V. / Slavin, A. / Zhu, X. / Chen, D. / Rong, H. / Enerson, B. / Mayo, M. / Sharma, K. / Browne, C.M. / Klaus, C.R. / Li, H. / Massa, G. / McDonald, A.A. / Shi, Y. / Sintchak, M. / Skouras, S. / Walther, D.M. / Yuan, K. / Zhang, Y. / Kelleher, J. / Guang, L. / Luo, X. / Mainolfi, N. / Weiss, M.M.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases.
Authors: Zheng, X. / Ji, N. / Campbell, V. / Slavin, A. / Zhu, X. / Chen, D. / Rong, H. / Enerson, B. / Mayo, M. / Sharma, K. / Browne, C.M. / Klaus, C.R. / Li, H. / Massa, G. / McDonald, A.A. / Shi, ...Authors: Zheng, X. / Ji, N. / Campbell, V. / Slavin, A. / Zhu, X. / Chen, D. / Rong, H. / Enerson, B. / Mayo, M. / Sharma, K. / Browne, C.M. / Klaus, C.R. / Li, H. / Massa, G. / McDonald, A.A. / Shi, Y. / Sintchak, M. / Skouras, S. / Walther, D.M. / Yuan, K. / Zhang, Y. / Kelleher, J. / Liu, G. / Luo, X. / Mainolfi, N. / Weiss, M.M.
History
DepositionJul 26, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 28, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _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: Protein cereblon
C: Protein cereblon
D: Protein cereblon
E: Protein cereblon
F: Protein cereblon
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,19043
Polymers75,2496
Non-polymers3,94237
Water5,495305
1
A: Protein cereblon
B: Protein cereblon
C: Protein cereblon
hetero molecules


  • defined by author&software
  • Evidence: gel filtration
  • 39.5 kDa, 3 polymers
Theoretical massNumber of molelcules
Total (without water)39,49119
Polymers37,6243
Non-polymers1,86716
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5410 Å2
ΔGint-130 kcal/mol
Surface area14240 Å2
MethodPISA
2
D: Protein cereblon
E: Protein cereblon
F: Protein cereblon
hetero molecules


  • defined by author&software
  • 39.7 kDa, 3 polymers
Theoretical massNumber of molelcules
Total (without water)39,69924
Polymers37,6243
Non-polymers2,07521
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6210 Å2
ΔGint-74 kcal/mol
Surface area14030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)141.470, 141.500, 141.590
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number22
Space group name H-MF222
Components on special symmetry positions
IDModelComponents
11A-637-

HOH

21F-650-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
22
33
44
55
66
77
88
99
1010
1111
1212
1313
1414
1515

NCS ensembles :
ID
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

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Components

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Protein , 1 types, 6 molecules ABCDEF

#1: Protein
Protein cereblon


Mass: 12541.449 Da / Num. of mol.: 6
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

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Non-polymers , 5 types, 342 molecules

#2: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-A1A0J / (3S)-3-(3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzimidazol-1-yl)piperidine-2,6-dione


Mass: 259.261 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C13H13N3O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#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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Details

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: 2.35 Å3/Da / Density % sol: 47.75 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 4.7
Details: 0.1M Acetate, pH4.7, 0.2M sodium chloride, 1.1M ammonium sulfate
PH range: 4.3-4.7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 27, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.6→42.72 Å / Num. obs: 92235 / % possible obs: 99.93 % / Redundancy: 1.9 % / Rmerge(I) obs: 0.03795 / Rpim(I) all: 0.03795 / Rrim(I) all: 0.05368 / Net I/σ(I): 12.25
Reflection shellResolution: 1.6→1.657 Å / Rmerge(I) obs: 0.2901 / Mean I/σ(I) obs: 2 / Num. unique obs: 9291 / CC1/2: 0.668 / CC star: 0.895 / Rpim(I) all: 0.2901 / Rrim(I) all: 0.4102 / % possible all: 99.92

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
XDSdata reduction
REFMACphasing
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→42.72 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.957 / SU B: 3.072 / SU ML: 0.05 / Cross valid method: THROUGHOUT / ESU R: 0.089 / ESU R Free: 0.081 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20491 4660 5 %RANDOM
Rwork0.15516 ---
obs0.15764 88354 99.88 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.754 Å2
Baniso -1Baniso -2Baniso -3
1-0.26 Å20 Å2-0 Å2
2---0.64 Å20 Å2
3---0.38 Å2
Refinement stepCycle: 1 / Resolution: 1.6→42.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4485 0 233 305 5023
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0135052
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174588
X-RAY DIFFRACTIONr_angle_refined_deg1.5951.6596865
X-RAY DIFFRACTIONr_angle_other_deg1.3061.57610711
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6165600
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.57923.118186
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.31915859
X-RAY DIFFRACTIONr_dihedral_angle_4_deg10.4861512
X-RAY DIFFRACTIONr_chiral_restr0.0730.2669
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025415
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021009
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.0592.7922361
X-RAY DIFFRACTIONr_mcbond_other3.0512.792360
X-RAY DIFFRACTIONr_mcangle_it3.654.1642965
X-RAY DIFFRACTIONr_mcangle_other3.6554.1652966
X-RAY DIFFRACTIONr_scbond_it3.6813.1462691
X-RAY DIFFRACTIONr_scbond_other3.683.1462692
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.4994.613898
X-RAY DIFFRACTIONr_long_range_B_refined4.71632.6555606
X-RAY DIFFRACTIONr_long_range_B_other4.71532.55575
X-RAY DIFFRACTIONr_rigid_bond_restr2.85539640
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A28350.08
12B28350.08
21A28930.11
22C28930.11
31A28110.09
32D28110.09
41A29260.08
42E29260.08
51A29290.11
52F29290.11
61B28210.09
62C28210.09
71B27900.09
72D27900.09
81B28420.09
82E28420.09
91B28290.09
92F28290.09
101C28180.09
102D28180.09
111C28210.1
112E28210.1
121C28890.1
122F28890.1
131D28760.09
132E28760.09
141D29000.08
142F29000.08
151E28530.09
152F28530.09
LS refinement shellResolution: 1.6→1.64 Å
RfactorNum. reflection% reflection
Rfree0.2 366 -
Rwork0.135 6427 -
obs--98.44 %

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