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- PDB-8vw4: Crystal structure of Cbl-b TKB bound to compound 26 -

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Basic information

Entry
Database: PDB / ID: 8vw4
TitleCrystal structure of Cbl-b TKB bound to compound 26
ComponentsE3 ubiquitin-protein ligase CBL-B
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Ubiquitin ligase / E3 / inhibitor / small molecule / TRANSFERASE / TRANSFERASE-TRANSFERASE 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
: / DI(HYDROXYETHYL)ETHER / E3 ubiquitin-protein ligase CBL-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsYu, C. / Murray, J. / Hsu, P.L.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding.
Authors: Liang, J. / Lambrecht, M.J. / Arenzana, T.L. / Aubert-Nicol, S. / Bao, L. / Broccatelli, F. / Cai, J. / Eidenschenk, C. / Everett, C. / Garner, T. / Gruber, F. / Haghshenas, P. / Huestis, M. ...Authors: Liang, J. / Lambrecht, M.J. / Arenzana, T.L. / Aubert-Nicol, S. / Bao, L. / Broccatelli, F. / Cai, J. / Eidenschenk, C. / Everett, C. / Garner, T. / Gruber, F. / Haghshenas, P. / Huestis, M.P. / Hsu, P.L. / Kou, P. / Jakalian, A. / Larouche-Gauthier, R. / Leclerc, J.P. / Leung, D.H. / Martin, A. / Murray, J. / Prangley, M. / Rutz, S. / Kakiuchi-Kiyota, S. / Satz, A.L. / Skelton, N.J. / Steffek, M. / Stoffler, D. / Sudhamsu, J. / Tan, S. / Wang, J. / Wang, S. / Wang, Q. / Wendorff, T.J. / Wichert, M. / Yadav, A. / Yu, C. / Wang, X.
History
DepositionJan 31, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release

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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
B: E3 ubiquitin-protein ligase CBL-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,99110
Polymers72,3832
Non-polymers1,6088
Water3,081171
1
A: E3 ubiquitin-protein ligase CBL-B
hetero molecules


  • defined by author
  • 37.1 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)37,0816
Polymers36,1921
Non-polymers8895
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase CBL-B
hetero molecules


  • defined by author
  • 36.9 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,9114
Polymers36,1921
Non-polymers7193
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)73.376, 88.466, 118.492
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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Protein , 1 types, 2 molecules AB

#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: 36191.551 Da / Num. of mol.: 2 / Fragment: Cbl-PTB domain, residues 36-343
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 , 5 types, 179 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-A1AEG / (7-methoxy-2-{2-[(1S,3S,4S)-3-(3-methoxy-2-methyl-5-nitrophenyl)-1-methyl-5-oxo-1,5-dihydroimidazo[1,5-a]pyridin-2(3H)-yl]-2-oxoethoxy}quinolin-8-yl)acetic acid


Mass: 588.565 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H28N4O9 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: C3H8O3
#5: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 171 / 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: 2.66 Å3/Da / Density % sol: 53.68 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.2 M NaCitrate, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 5, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→41.44 Å / Num. obs: 30849 / % possible obs: 99.56 % / Redundancy: 6.5 % / Biso Wilson estimate: 40.71 Å2 / CC1/2: 0.996 / Net I/σ(I): 11.19
Reflection shellResolution: 2.4→2.486 Å / Mean I/σ(I) obs: 1.15 / Num. unique obs: 3014 / CC1/2: 0.488

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→41.44 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2531 1586 5.15 %
Rwork0.1988 --
obs0.2016 30826 99.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.4→41.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5012 0 113 171 5296
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.004
X-RAY DIFFRACTIONf_angle_d0.694
X-RAY DIFFRACTIONf_dihedral_angle_d14.0431959
X-RAY DIFFRACTIONf_chiral_restr0.045739
X-RAY DIFFRACTIONf_plane_restr0.005906
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.470.34261260.31242544X-RAY DIFFRACTION98
2.47-2.560.3391610.28052599X-RAY DIFFRACTION99
2.56-2.660.33191270.27682633X-RAY DIFFRACTION99
2.66-2.780.36081330.27532636X-RAY DIFFRACTION99
2.78-2.930.28961560.25132622X-RAY DIFFRACTION100
2.93-3.120.28641400.22942642X-RAY DIFFRACTION100
3.12-3.360.26671260.20862684X-RAY DIFFRACTION100
3.36-3.690.25351490.18762665X-RAY DIFFRACTION100
3.69-4.230.22641710.16362661X-RAY DIFFRACTION100
4.23-5.320.20391360.14672717X-RAY DIFFRACTION100
5.32-41.440.20811610.1722837X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -17.0511 Å / Origin y: 3.1294 Å / Origin z: -4.3606 Å
111213212223313233
T0.3036 Å2-0.0353 Å2-0.0263 Å2-0.2335 Å2-0.0072 Å2--0.2986 Å2
L0.6756 °2-0.3576 °2-0.6763 °2-0.2338 °20.1572 °2--1.2913 °2
S0.1167 Å °-0.039 Å °0.0513 Å °-0.0204 Å °0.0109 Å °-0.0423 Å °-0.1519 Å °0.0504 Å °-0.1185 Å °
Refinement TLS groupSelection details: all

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