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

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Basic information

Entry
Database: PDB / ID: 8qng
TitleCrystal structure of the E3 ubiquitin ligase Cbl-b with an allosteric inhibitor (benzodiazepine HTS hit compound 1)
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 / 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-W89 / E3 ubiquitin-protein ligase CBL-B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.197 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)46,4185
Polymers45,8101
Non-polymers6084
Water36020
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.578, 72.045, 94.786
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-W89 / 2-(morpholin-4-ylmethyl)-~{N}-[(3~{S})-2-oxidanylidene-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]benzamide


Mass: 454.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H26N4O3 / 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 / Water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.07 Å3/Da / Density % sol: 40.62 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 9 % PEG8000, 0.05 M MgAcetate, 0.05 M PCTP pH 7.5

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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: Mar 10, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.197→47.944 Å / Num. obs: 11958 / % possible obs: 59.7 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.082 / Rpim(I) all: 0.034 / Rrim(I) all: 0.089 / Net I/σ(I): 13.3 / Num. measured all: 79871
Reflection shellResolution: 2.197→2.458 Å / % possible obs: 10.6 % / Redundancy: 6.2 % / Rmerge(I) obs: 1.109 / Num. measured all: 3714 / Num. unique obs: 598 / Rpim(I) all: 0.481 / Rrim(I) all: 1.211 / Net I/σ(I) obs: 1.6

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (8-JUN-2022)refinement
Aimlessdata scaling
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.197→47.94 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.861 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.388
RfactorNum. reflection% reflectionSelection details
Rfree0.2949 586 4.91 %RANDOM
Rwork0.2187 ---
obs0.2224 11942 59.6 %-
Displacement parametersBiso mean: 60.24 Å2
Baniso -1Baniso -2Baniso -3
1--0.4751 Å20 Å20 Å2
2---6.8079 Å20 Å2
3---7.2831 Å2
Refine analyzeLuzzati coordinate error obs: 0.34 Å
Refinement stepCycle: LAST / Resolution: 2.197→47.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3087 0 37 20 3144
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0083200HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.914328HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1120SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes536HARMONIC5
X-RAY DIFFRACTIONt_it3200HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.89
X-RAY DIFFRACTIONt_other_torsion20.44
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_contact2643SEMIHARMONIC4
LS refinement shellResolution: 2.2→2.4 Å / Total num. of bins used: 30
RfactorNum. reflection% reflection
Rfree0.3699 -5.83 %
Rwork0.2831 388 -
all0.2885 412 -
obs--8.82 %
Refinement TLS params.Method: refined / Origin x: 19.7014 Å / Origin y: 15.9838 Å / Origin z: 28.2176 Å
111213212223313233
T-0.1258 Å20.0241 Å20.079 Å2--0.2452 Å2-0.0048 Å2---0.0606 Å2
L2.381 °20.398 °2-0.2123 °2-3.1367 °2-0.0184 °2--1.6763 °2
S0.1927 Å °-0.054 Å °-0.0878 Å °-0.0328 Å °-0.1284 Å °0.0975 Å °-0.0773 Å °-0.0558 Å °-0.0643 Å °
Refinement TLS groupSelection details: { A|* }

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