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- PDB-8gcy: Co-crystal structure of CBL-B in complex with N-Aryl isoindolin-1... -

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Basic information

Entry
Database: PDB / ID: 8gcy
TitleCo-crystal structure of CBL-B in complex with N-Aryl isoindolin-1-one inhibitor
ComponentsE3 ubiquitin-protein ligase CBL-B
KeywordsLIGASE/LIGASE INHIBITOR / E3 ligase / CBL-B / inhibitor / SGC / LIGASE / LIGASE-LIGASE INHIBITOR complex
Function / homology
Function and homology information


regulation of platelet-derived growth factor receptor-alpha signaling pathway / T cell anergy / positive regulation of T cell anergy / CD4-positive, alpha-beta T cell proliferation / negative regulation of CD4-positive, alpha-beta T cell proliferation / negative regulation of T cell receptor signaling pathway / NLS-bearing protein import into nucleus / phosphotyrosine residue binding / positive regulation of protein ubiquitination / protein catabolic process ...regulation of platelet-derived growth factor receptor-alpha signaling pathway / T cell anergy / positive regulation of T cell anergy / CD4-positive, alpha-beta T cell proliferation / negative regulation of CD4-positive, alpha-beta T cell proliferation / negative regulation of T cell receptor signaling pathway / NLS-bearing protein import into nucleus / phosphotyrosine residue binding / positive regulation of protein ubiquitination / protein catabolic process / RING-type E3 ubiquitin transferase / receptor tyrosine kinase binding / SH3 domain binding / positive regulation of protein catabolic process / ubiquitin protein ligase activity / Antigen processing: Ubiquitination & Proteasome degradation / T cell receptor signaling pathway / protein ubiquitination / intracellular signal transduction / immune response / membrane raft / calcium ion binding / signal transduction / zinc ion binding / nucleoplasm / plasma membrane / cytosol
Similarity search - Function
E3 ubiquitin-protein ligase CBL-B, RING finger, HC subclass / Adaptor protein Cbl, N-terminal helical / Adaptor protein Cbl, EF hand-like / Adaptor protein Cbl, SH2-like domain / Adaptor protein Cbl, PTB domain / Adaptor protein Cbl / CBL proto-oncogene N-terminal domain 1 / CBL proto-oncogene N-terminus, EF hand-like domain / CBL proto-oncogene N-terminus, SH2-like domain / Cbl-type phosphotyrosine-binding (Cbl-PTB) domain profile. ...E3 ubiquitin-protein ligase CBL-B, RING finger, HC subclass / Adaptor protein Cbl, N-terminal helical / Adaptor protein Cbl, EF hand-like / Adaptor protein Cbl, SH2-like domain / Adaptor protein Cbl, PTB domain / Adaptor protein Cbl / CBL proto-oncogene N-terminal domain 1 / CBL proto-oncogene N-terminus, EF hand-like domain / CBL proto-oncogene N-terminus, SH2-like domain / Cbl-type phosphotyrosine-binding (Cbl-PTB) domain profile. / Adaptor protein Cbl, N-terminal domain superfamily / Ubiquitin associated domain / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / SH2 domain superfamily / EF-hand domain pair / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Chem-Z3N / E3 ubiquitin-protein ligase CBL-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.81 Å
AuthorsKimani, S. / Zeng, H. / Dong, A. / Li, Y. / Santhakumar, V. / Arrowsmith, C.H. / Edwards, A.M. / Halabelian, L. / Structural Genomics Consortium (SGC)
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: Commun Biol / Year: 2023
Title: The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition.
Authors: Kimani, S.W. / Perveen, S. / Szewezyk, M. / Zeng, H. / Dong, A. / Li, F. / Ghiabi, P. / Li, Y. / Chau, I. / Arrowsmith, C.H. / Barsyte-Lovejoy, D. / Santhakumar, V. / Vedadi, M. / Halabelian, L.
History
DepositionMar 3, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase CBL-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)45,9797
Polymers45,1531
Non-polymers8276
Water2,558142
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.937, 76.093, 105.464
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein E3 ubiquitin-protein ligase CBL-B / Casitas B-lineage lymphoma proto-oncogene b / RING finger protein 56 / RING-type E3 ubiquitin ...Casitas B-lineage lymphoma proto-oncogene b / RING finger protein 56 / RING-type E3 ubiquitin transferase CBL-B / SH3-binding protein CBL-B / Signal transduction protein CBL-B


Mass: 45152.605 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CBLB, RNF56, Nbla00127 / Production host: Escherichia coli (E. coli)
References: UniProt: Q13191, RING-type E3 ubiquitin transferase

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Non-polymers , 6 types, 148 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-Z3N / 2-{3-[(1s,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-6-{[(3S)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one


Mass: 537.619 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H34F3N5O / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#6: Chemical ChemComp-UNX / UNKNOWN ATOM OR ION


Num. of mol.: 1 / Source method: obtained synthetically
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 142 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.13 Å3/Da / Density % sol: 42.25 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 0.1 M Imidazole, 0.1 M MES monohydrate pH 6.5 0.09 M Sodium nitrate, 0.09 M Sodium phosphate dibasic, 0.09M Ammonium sulfate 12.5% v/v MPD; 12.5% PEG1000; 12.5% w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Feb 11, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 1.81→50 Å / Num. obs: 35624 / % possible obs: 98.6 % / Redundancy: 10.9 % / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.064 / Χ2: 0.957 / Net I/σ(I): 36
Reflection shellResolution: 1.81→1.84 Å / Redundancy: 9.9 % / Rmerge(I) obs: 0.94 / Num. unique obs: 1755 / CC1/2: 0.827 / CC star: 0.951 / Χ2: 0.638 / % possible all: 98.3

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Processing

Software
NameVersionClassification
HKL-3000data scaling
REFMACREFMAC 5.8.0258refinement
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.81→43.68 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.943 / SU B: 3.58 / SU ML: 0.107 / Cross valid method: THROUGHOUT / ESU R: 0.142 / ESU R Free: 0.131 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22962 1795 5 %RANDOM
Rwork0.19491 ---
obs0.19669 33780 98.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.702 Å2
Baniso -1Baniso -2Baniso -3
1--1.2 Å20 Å20 Å2
2--2.69 Å2-0 Å2
3----1.49 Å2
Refinement stepCycle: 1 / Resolution: 1.81→43.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2966 0 51 142 3159
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0133183
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172851
X-RAY DIFFRACTIONr_angle_refined_deg1.4511.6414335
X-RAY DIFFRACTIONr_angle_other_deg1.3341.596594
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4715392
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.06422.436156
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.88215512
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0811516
X-RAY DIFFRACTIONr_chiral_restr0.0730.2412
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.023636
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02702
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_it3.0533.4541547
X-RAY DIFFRACTIONr_mcbond_other3.0393.4521546
X-RAY DIFFRACTIONr_mcangle_it4.1475.1631946
X-RAY DIFFRACTIONr_mcangle_other4.1485.1641947
X-RAY DIFFRACTIONr_scbond_it3.353.6721636
X-RAY DIFFRACTIONr_scbond_other3.3293.6691633
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.9735.392382
X-RAY DIFFRACTIONr_long_range_B_refined6.61540.053630
X-RAY DIFFRACTIONr_long_range_B_other6.62139.9873610
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.81→1.853 Å
RfactorNum. reflection% reflection
Rfree0.265 130 -
Rwork0.273 2358 -
obs--94.46 %

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