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- PDB-8vw5: Crystal structure of Cbl-b TKB bound to compound 2 -

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Basic information

Entry
Database: PDB / ID: 8vw5
TitleCrystal structure of Cbl-b TKB bound to compound 2
Components(E3 ubiquitin-protein ligase CBL- ...) x 2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Ubiquitin ligase / E3 / inhibitor / 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
: / E3 ubiquitin-protein ligase CBL-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.76 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)73,8907
Polymers72,3702
Non-polymers1,5205
Water11,097616
1
A: E3 ubiquitin-protein ligase CBL-B
hetero molecules


  • defined by author
  • 37 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)36,9784
Polymers36,2061
Non-polymers7723
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)36,9123
Polymers36,1651
Non-polymers7482
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.198, 56.820, 71.568
Angle α, β, γ (deg.)102.90, 96.55, 111.97
Int Tables number1
Space group name H-MP1

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Components

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E3 ubiquitin-protein ligase CBL- ... , 2 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: 36205.539 Da / Num. of mol.: 1 / 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
#2: 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: 36164.527 Da / Num. of mol.: 1 / 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 , 4 types, 621 molecules

#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-A1AD4 / [5-(2-{(2R,5S)-2-[2-(carboxymethoxy)-3-methoxy-5-nitrophenyl]-3,5-dimethyl-4-oxoimidazolidin-1-yl}-2-oxoethyl)-3,6-dimethoxy-9,9-dimethyl-9H-xanthen-4-yl]acetic acid


Mass: 707.681 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C35H37N3O13 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 616 / 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: 2.74 Å3/Da / Density % sol: 55.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Ca(OAc)2, 0.1 M NaCacodylate pH 6.5, 18% PEG8000

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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: Oct 5, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.76→35.88 Å / Num. obs: 72083 / % possible obs: 84.34 % / Redundancy: 2 % / CC1/2: 0.998 / Net I/σ(I): 9.35
Reflection shellResolution: 1.76→1.83 Å / Mean I/σ(I) obs: 0.98 / Num. unique obs: 6009 / CC1/2: 0.53

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX(1.20.1_4487: ???)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.76→35.88 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2041 3101 4.84 %
Rwork0.1753 --
obs0.1767 64022 84.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.76→35.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5007 0 105 616 5728
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0055266
X-RAY DIFFRACTIONf_angle_d0.6387140
X-RAY DIFFRACTIONf_dihedral_angle_d13.4272018
X-RAY DIFFRACTIONf_chiral_restr0.044749
X-RAY DIFFRACTIONf_plane_restr0.005963
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.76-1.790.38681280.41292377X-RAY DIFFRACTION71
1.79-1.820.39851390.39692739X-RAY DIFFRACTION84
1.82-1.850.38561270.36242674X-RAY DIFFRACTION81
1.85-1.880.32381430.3162683X-RAY DIFFRACTION82
1.88-1.920.32161260.29632627X-RAY DIFFRACTION80
1.92-1.960.28281710.27982835X-RAY DIFFRACTION87
1.96-20.29461530.26082826X-RAY DIFFRACTION87
2-2.050.25471360.2232876X-RAY DIFFRACTION87
2.05-2.10.24041400.20342834X-RAY DIFFRACTION86
2.1-2.160.24151240.19152791X-RAY DIFFRACTION85
2.16-2.220.2471410.18162730X-RAY DIFFRACTION83
2.22-2.290.22691370.17592648X-RAY DIFFRACTION81
2.29-2.370.19861660.1662786X-RAY DIFFRACTION85
2.37-2.470.21281430.16742866X-RAY DIFFRACTION88
2.47-2.580.18831380.16272895X-RAY DIFFRACTION87
2.58-2.720.20821490.16632808X-RAY DIFFRACTION86
2.72-2.890.1841410.17172755X-RAY DIFFRACTION84
2.89-3.110.21151420.16942744X-RAY DIFFRACTION84
3.11-3.420.19651370.15582926X-RAY DIFFRACTION89
3.42-3.920.15121260.15272847X-RAY DIFFRACTION86
3.92-4.930.15741490.12962715X-RAY DIFFRACTION83
4.93-35.880.18371450.15182939X-RAY DIFFRACTION89
Refinement TLS params.Method: refined / Origin x: -6.448 Å / Origin y: -9.2001 Å / Origin z: 35.8321 Å
111213212223313233
T0.1858 Å2-0.0127 Å2-0.021 Å2-0.2163 Å2-0.0183 Å2--0.1896 Å2
L0.4552 °20.2991 °2-0.2485 °2-0.4783 °2-0.3504 °2--0.7484 °2
S0.0318 Å °-0.0293 Å °0.0412 Å °0.0353 Å °-0.0324 Å °0.0412 Å °-0.0272 Å °0.0431 Å °0.0048 Å °
Refinement TLS groupSelection details: all

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