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- PDB-8qtk: Crystal structure of CBL-b in complex with an allosteric inhibito... -

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Basic information

Entry
Database: PDB / ID: 8qtk
TitleCrystal structure of CBL-b in complex with an allosteric inhibitor (compound 31)
ComponentsE3 ubiquitin-protein ligase CBL-B
KeywordsLIGASE / E3 Ubiquitin ligase / allosteric inhibitor
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 / RING-type E3 ubiquitin transferase ...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 / RING-type E3 ubiquitin transferase / protein catabolic process / 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-WX9 / E3 ubiquitin-protein ligase CBL-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.873 Å
AuthorsSchimpl, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery, Optimization, and Biological Evaluation of Arylpyridones as Cbl-b Inhibitors.
Authors: Mfuh, A.M. / Boerth, J.A. / Bommakanti, G. / Chan, C. / Chinn, A.J. / Code, E. / Fricke, P.J. / Giblin, K.A. / Gohlke, A. / Hansel, C. / Hariparsad, N. / Hughes, S.J. / Jin, M. / Kantae, V. ...Authors: Mfuh, A.M. / Boerth, J.A. / Bommakanti, G. / Chan, C. / Chinn, A.J. / Code, E. / Fricke, P.J. / Giblin, K.A. / Gohlke, A. / Hansel, C. / Hariparsad, N. / Hughes, S.J. / Jin, M. / Kantae, V. / Kavanagh, S.L. / Lamb, M.L. / Lane, J. / Moore, R. / Puri, T. / Quinn, T.R. / Reddy, I. / Robb, G.R. / Robbins, K.J. / Gancedo Rodrigo, M. / Schimpl, M. / Singh, B. / Singh, M. / Tang, H. / Thomson, C. / Walsh, J.J. / Ware, J. / Watson, I.D.G. / Ye, M.W. / Wrigley, G.L. / Zhang, A.X. / Zhang, Y. / Grimster, N.P.
History
DepositionOct 12, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 24, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 7, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)46,4605
Polymers45,8101
Non-polymers6504
Water1,69394
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area18470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.268, 74.966, 97.560
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein E3 ubiquitin-protein ligase CBL-B


Mass: 45809.512 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CBLB / Production host: Escherichia coli (E. coli) / References: UniProt: Q13191
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-WX9 / 3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-1-[(1S)-1-(1-methylpyrazol-4-yl)ethyl]-5-(trifluoromethyl)pyridin-2-one


Mass: 496.527 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H27F3N6O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 94 / Source method: isolated from a natural source / Formula: H2O
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: 2.29 Å3/Da / Density % sol: 46.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 8-11 % PEG8000, 2.5 % MPD, 0.05 M MgAcetate, 0.05 M PCTP pH 8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 4, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.873→59.443 Å / Num. obs: 22343 / % possible obs: 63.3 % / Redundancy: 9.5 % / Rmerge(I) obs: 0.047 / Rpim(I) all: 0.016 / Rrim(I) all: 0.049 / Net I/σ(I): 19.8 / Num. measured all: 211452
Reflection shellResolution: 1.873→2.062 Å / % possible obs: 12.8 % / Redundancy: 7.6 % / Rmerge(I) obs: 1.106 / Num. measured all: 8543 / Num. unique obs: 1118 / Rpim(I) all: 0.427 / Rrim(I) all: 1.187 / Net I/σ(I) obs: 1.6

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (26-JUL-2023)refinement
STARANISOdata scaling
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.873→27.48 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.912 / SU R Cruickshank DPI: 0.267 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.269 / SU Rfree Blow DPI: 0.22 / SU Rfree Cruickshank DPI: 0.222
RfactorNum. reflection% reflectionSelection details
Rfree0.2681 1107 4.96 %RANDOM
Rwork0.2093 ---
obs0.2121 22326 63.3 %-
Displacement parametersBiso mean: 51.07 Å2
Baniso -1Baniso -2Baniso -3
1--0.8424 Å20 Å20 Å2
2---3.7999 Å20 Å2
3---4.6424 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 1.873→27.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3100 0 39 94 3233
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0093215HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.894355HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1119SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes538HARMONIC5
X-RAY DIFFRACTIONt_it3215HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.85
X-RAY DIFFRACTIONt_other_torsion16.86
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion410SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2668SEMIHARMONIC4
LS refinement shellResolution: 1.873→1.98 Å
RfactorNum. reflection% reflection
Rfree0.3923 -4.03 %
Rwork0.2916 429 -
obs--8.18 %
Refinement TLS params.Method: refined / Origin x: 19.8069 Å / Origin y: 15.9134 Å / Origin z: 28.7499 Å
111213212223313233
T-0.1335 Å20.0369 Å20.021 Å2--0.1718 Å20.0277 Å2---0.0737 Å2
L0.4944 °2-0.2578 °2-0.3148 °2-3.0271 °2-0.3672 °2--1.5959 °2
S0.1686 Å °-0.0037 Å °-0.0665 Å °0.0485 Å °-0.1045 Å °0.119 Å °-0.2199 Å °-0.0607 Å °-0.0641 Å °
Refinement TLS groupSelection details: { A|* }

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