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- PDB-9fqj: E3 ligase Cbl-b in complex with a carbamate scaffold inhibitor (c... -

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Basic information

Entry
Database: PDB / ID: 9fqj
TitleE3 ligase Cbl-b in complex with a carbamate scaffold inhibitor (compound 12)
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 / 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: 1.563 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

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)92,65910
Polymers91,6192
Non-polymers1,0408
Water8,413467
1
A: E3 ubiquitin-protein ligase CBL-B
hetero molecules


  • defined by author
  • Evidence: gel filtration
  • 46.3 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)46,3305
Polymers45,8101
Non-polymers5204
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase CBL-B
hetero molecules


  • defined by author
  • 46.3 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)46,3305
Polymers45,8101
Non-polymers5204
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.775, 74.524, 105.981
Angle α, β, γ (deg.)90.00, 104.84, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 45809.512 Da / Num. of mol.: 2 / Mutation: EC:2.3.2.27
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-A1IE5 / 2-cyclopropyl-6-methyl-~{N}-[3-[(6~{S})-6-methyl-2-oxidanylidene-1,3-oxazinan-6-yl]phenyl]pyrimidine-4-carboxamide


Mass: 366.414 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H22N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


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


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 467 / 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: 2.37 Å3/Da / Density % sol: 48 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 11 % PEG8000, 0.05 M Mg Acetate, 5 % MPD, 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: 0.95374 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Mar 7, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95374 Å / Relative weight: 1
ReflectionResolution: 1.563→102.445 Å / Num. obs: 84190 / % possible obs: 69.8 % / Redundancy: 5 % / Rmerge(I) obs: 0.086 / Rpim(I) all: 0.041 / Rrim(I) all: 0.096 / Net I/σ(I): 8.9 / Num. measured all: 420999
Reflection shellResolution: 1.563→1.715 Å / % possible obs: 14.5 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.942 / Num. measured all: 20596 / Num. unique obs: 4209 / Rpim(I) all: 0.464 / Rrim(I) all: 1.054 / 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
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.563→102.44 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.942 / SU R Cruickshank DPI: 0.116 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.117 / SU Rfree Blow DPI: 0.11 / SU Rfree Cruickshank DPI: 0.111
RfactorNum. reflection% reflectionSelection details
Rfree0.2223 4165 4.95 %RANDOM
Rwork0.1926 ---
obs0.194 84179 69.7 %-
Displacement parametersBiso mean: 25.01 Å2
Baniso -1Baniso -2Baniso -3
1-0.4287 Å20 Å21.3142 Å2
2---1.5797 Å20 Å2
3---1.151 Å2
Refine analyzeLuzzati coordinate error obs: 0.22 Å
Refinement stepCycle: 1 / Resolution: 1.563→102.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6220 0 60 467 6747
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016428HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.898692HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2262SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1078HARMONIC5
X-RAY DIFFRACTIONt_it6428HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.35
X-RAY DIFFRACTIONt_other_torsion15.93
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion820SEMIHARMONIC5
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_contact6027SEMIHARMONIC4
LS refinement shellResolution: 1.563→1.66 Å
RfactorNum. reflection% reflection
Rfree0.2593 -4.16 %
Rwork0.2442 1614 -
obs--8.64 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.31120.0354-0.02580.65710.21420.63430.012-0.028-0.0301-0.0515-0.01140.0199-0.0508-0.0655-0.0006-0.08960.02830.0296-0.1090.0039-0.065619.596715.63564.3225
20.3975-0.051-0.03380.5462-0.0180.6814-0.0115-0.04920.01340.0166-0.0014-0.01410.03980.02540.0129-0.08940.01220.0105-0.10930.0081-0.089123.686615.80255.5161
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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