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- PDB-9fqh: E3 ligase Cbl-b in complex with a triazolone core inhibitor (comp... -

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Basic information

Entry
Database: PDB / ID: 9fqh
TitleE3 ligase Cbl-b in complex with a triazolone core inhibitor (compound 1)
ComponentsE3 ubiquitin-protein ligase CBL-B
KeywordsLIGASE
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 / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / Ubiquitin associated domain / 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: 1.786 Å
AuthorsSchimpl, M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Accelerated Discovery of Carbamate Cbl-b Inhibitors Using Generative AI Models and Structure-Based Drug Design.
Authors: Quinn, T.R. / Giblin, K.A. / Thomson, C. / Boerth, J.A. / Bommakanti, G. / Braybrooke, E. / Chan, C. / Chinn, A.J. / Code, E. / Cui, C. / Fan, Y. / Grimster, N.P. / Kohara, K. / Lamb, M.L. / ...Authors: Quinn, T.R. / Giblin, K.A. / Thomson, C. / Boerth, J.A. / Bommakanti, G. / Braybrooke, E. / Chan, C. / Chinn, A.J. / Code, E. / Cui, C. / Fan, Y. / Grimster, N.P. / Kohara, K. / Lamb, M.L. / Ma, L. / Mfuh, A.M. / Robb, G.R. / Robbins, K.J. / Schimpl, M. / Tang, H. / Ware, J. / Wrigley, G.L. / Xue, L. / Zhang, Y. / Zhu, H. / Hughes, S.J.
History
DepositionJun 17, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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)46,5035
Polymers45,8101
Non-polymers6934
Water79344
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 area18260 Å2
Unit cell
Length a, b, c (Å)56.811, 73.873, 93.608
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-A1IEW / 8-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-3-[[(3~{S})-3-methylpiperidin-1-yl]methyl]-5-(trifluoromethyl)-1$l^{4},7,8-triazabicyclo[4.3.0]nona-1(6),2,4-trien-9-one


Mass: 539.595 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H32F3N7O / 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.: 44 / 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: 2.14 Å3/Da / Density % sol: 42.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 9 % PEG8000, 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: I24 / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Apr 26, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 1.786→19.768 Å / Num. obs: 27410 / % possible obs: 72 % / Redundancy: 5.6 % / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.036 / Rrim(I) all: 0.085 / Net I/σ(I): 11.4 / Num. measured all: 152844
Reflection shellResolution: 1.786→1.92 Å / % possible obs: 18.8 % / Redundancy: 5.2 % / Rmerge(I) obs: 1.33 / Num. measured all: 7094 / Num. unique obs: 1371 / Rpim(I) all: 0.641 / Rrim(I) all: 1.482 / Net I/σ(I) obs: 1.6

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (24-FEB-2021)refinement
STARANISOdata scaling
XDSdata reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.786→19.768 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.928 / SU R Cruickshank DPI: 0.205 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.201 / SU Rfree Blow DPI: 0.166 / SU Rfree Cruickshank DPI: 0.169
RfactorNum. reflection% reflectionSelection details
Rfree0.2495 1343 4.9 %RANDOM
Rwork0.2214 ---
obs0.2228 27381 71.9 %-
Displacement parametersBiso mean: 45.08 Å2
Baniso -1Baniso -2Baniso -3
1-1.3371 Å20 Å20 Å2
2---1.2043 Å20 Å2
3----0.1328 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: 1 / Resolution: 1.786→19.768 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3092 0 42 44 3178
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0083211HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.894351HARMONIC2
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_planes535HARMONIC5
X-RAY DIFFRACTIONt_it3211HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.9
X-RAY DIFFRACTIONt_other_torsion17.17
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion411SEMIHARMONIC5
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_contact2728SEMIHARMONIC4
LS refinement shellResolution: 1.79→1.87 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.321 -4.01 %
Rwork0.3191 526 -
all0.3192 548 -
obs--11.15 %
Refinement TLS params.Method: refined / Origin x: 19.6852 Å / Origin y: 16.215 Å / Origin z: 27.9398 Å
111213212223313233
T-0.0218 Å20.0398 Å20.0018 Å2--0.0756 Å20.0173 Å2---0.0726 Å2
L0.1972 °20.0597 °2-0.1519 °2-1.1898 °2-0.0338 °2--1.3278 °2
S0.062 Å °0.0203 Å °-0.0708 Å °-0.0034 Å °-0.0274 Å °-0.002 Å °-0.1915 Å °-0.0582 Å °-0.0346 Å °
Refinement TLS groupSelection details: { A|* }

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