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- PDB-8qni: Crystal structure of the E3 ubiquitin ligase Cbl-b with an allost... -

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Basic information

Entry
Database: PDB / ID: 8qni
TitleCrystal structure of the E3 ubiquitin ligase Cbl-b with an allosteric inhibitor (benzodiazepine compound 25)
ComponentsE3 ubiquitin-protein ligase CBL-B
KeywordsLIGASE / E3 Ubiquitin ligase / allosteric inhibition / structure based drug design
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 / intracellular signal transduction / protein ubiquitination / 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-W7R / E3 ubiquitin-protein ligase CBL-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.483 Å
AuthorsSchimpl, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Discovery of a Novel Benzodiazepine Series of Cbl-b Inhibitors for the Enhancement of Antitumor Immunity.
Authors: Boerth, J.A. / Chinn, A.J. / Schimpl, M. / Bommakanti, G. / Chan, C. / Code, E.L. / Giblin, K.A. / Gohlke, A. / Hansel, C.S. / Jin, M. / Kavanagh, S.L. / Lamb, M.L. / Lane, J.S. / Larner, C. ...Authors: Boerth, J.A. / Chinn, A.J. / Schimpl, M. / Bommakanti, G. / Chan, C. / Code, E.L. / Giblin, K.A. / Gohlke, A. / Hansel, C.S. / Jin, M. / Kavanagh, S.L. / Lamb, M.L. / Lane, J.S. / Larner, C.J.B. / Mfuh, A.M. / Moore, R.K. / Puri, T. / Quinn, T.R. / Ye, M. / Robbins, K.J. / Gancedo-Rodrigo, M. / Tang, H. / Walsh, J. / Ware, J. / Wrigley, G.L. / Reddy, I.K. / Zhang, Y. / Grimster, N.P.
History
DepositionSep 26, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 6, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Jan 3, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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)46,4335
Polymers45,8101
Non-polymers6234
Water21612
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area18450 Å2
Unit cell
Length a, b, c (Å)57.125, 73.364, 102.741
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-W7R / 2-[[(2~{S})-2-methylmorpholin-4-yl]methyl]-~{N}-[(3~{S})-2-oxidanylidene-5-phenyl-1,3-dihydropyrido[3,4-e][1,4]diazepin-3-yl]benzamide


Mass: 469.535 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ZN / ZINC ION


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


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 2.35 Å3/Da / Density % sol: 47.66 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 11 % PEG8000, 5 % MPD, 0.05 M MgAcetate, 0.05 M PCPT pH 8.0

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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: Aug 4, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.483→51.37 Å / Num. obs: 11896 / % possible obs: 75.2 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.076 / Rpim(I) all: 0.032 / Rrim(I) all: 0.083 / Net I/σ(I): 14.5 / Num. measured all: 79046
Reflection shellResolution: 2.483→2.747 Å / % possible obs: 14.7 % / Redundancy: 5.9 % / Rmerge(I) obs: 1.432 / Num. measured all: 3544 / Num. unique obs: 596 / Rpim(I) all: 0.625 / Rrim(I) all: 1.567 / Net I/σ(I) obs: 1.2

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
STARANISOdata scaling
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.483→51.37 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.893 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.391
RfactorNum. reflection% reflectionSelection details
Rfree0.2859 579 4.87 %RANDOM
Rwork0.2181 ---
obs0.2213 11888 75.2 %-
Displacement parametersBiso mean: 74.43 Å2
Baniso -1Baniso -2Baniso -3
1-0.1823 Å20 Å20 Å2
2---6.6746 Å20 Å2
3---6.4923 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.483→51.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3044 0 38 12 3094
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0073157HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.94267HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1110SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes528HARMONIC5
X-RAY DIFFRACTIONt_it3157HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.68
X-RAY DIFFRACTIONt_other_torsion19.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion403SEMIHARMONIC5
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_contact2520SEMIHARMONIC4
LS refinement shellResolution: 2.483→2.73 Å
RfactorNum. reflection% reflection
Rfree0.3204 -5.65 %
Rwork0.3096 401 -
obs--11.04 %
Refinement TLS params.Method: refined / Origin x: 20.2184 Å / Origin y: 12.7923 Å / Origin z: 30.1172 Å
111213212223313233
T-0.1292 Å20.061 Å20.0178 Å2--0.1934 Å20.0456 Å2---0.0459 Å2
L2.0866 °20.4382 °2-0.1168 °2-3.1597 °20.2873 °2--1.3795 °2
S0.1163 Å °-0.1218 Å °-0.05 Å °0.1892 Å °-0.1012 Å °0.1656 Å °-0.0158 Å °-0.2295 Å °-0.0151 Å °
Refinement TLS groupSelection details: { A|* }

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