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- PDB-9wdh: Crystal Structure of CBL-B in Complex with a Potent Inhibitor Dem... -

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Basic information

Entry
Database: PDB / ID: 9wdh
TitleCrystal Structure of CBL-B in Complex with a Potent Inhibitor Demonstrating In Vivo Efficacy
ComponentsE3 ubiquitin-protein ligase CBL-B
KeywordsLIGASE / Inhibitor
Function / homology
Function and homology information


regulation of platelet-derived growth factor receptor-alpha signaling pathway / NLS-bearing protein import into nucleus / negative regulation of T cell activation / negative regulation of epidermal growth factor receptor signaling pathway / negative regulation of T cell receptor signaling pathway / protein K63-linked ubiquitination / phosphotyrosine residue binding / receptor tyrosine kinase binding / RING-type E3 ubiquitin transferase / ubiquitin protein ligase activity ...regulation of platelet-derived growth factor receptor-alpha signaling pathway / NLS-bearing protein import into nucleus / negative regulation of T cell activation / negative regulation of epidermal growth factor receptor signaling pathway / negative regulation of T cell receptor signaling pathway / protein K63-linked ubiquitination / phosphotyrosine residue binding / receptor tyrosine kinase binding / RING-type E3 ubiquitin transferase / ubiquitin protein ligase activity / Antigen processing: Ubiquitination & Proteasome degradation / cell surface receptor signaling pathway / protein stabilization / membrane raft / calcium ion binding / signal transduction / zinc ion binding / 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 / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Ring finger / SH2 domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / 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: 2.8 Å
AuthorsSun, G. / Wang, H. / Liu, C. / Zhang, B. / Wang, Y. / Xin, B. / Jiang, D. / Wang, H. / Huang, B.
Funding support China, 1items
OrganizationGrant numberCountry
Other governmentZ241100007724005 China
CitationJournal: To Be Published
Title: A Unified 3D Molecular Generation Platform for Novel Scaffold Discovery and Hit-to-Lead Optimization Leading to Cbl-b Inhibitor Discovery with In Vivo Efficacy
Authors: Wang, H. / Sun, G. / Zhang, B. / Wang, Y. / Xin, B. / Yang, M. / Liu, C. / Zhou, F. / Liu, Z. / Jiang, D. / Wang, H. / Zhou, W. / Huang, B.
History
DepositionAug 19, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 26, 2026Provider: repository / Type: Initial release

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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)92,7159
Polymers91,3892
Non-polymers1,3267
Water3,243180
1
A: E3 ubiquitin-protein ligase CBL-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3905
Polymers45,6941
Non-polymers6964
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area20 Å2
ΔGint-3 kcal/mol
Surface area18500 Å2
MethodPISA
2
B: E3 ubiquitin-protein ligase CBL-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3254
Polymers45,6941
Non-polymers6303
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area20 Å2
ΔGint-3 kcal/mol
Surface area18490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.050, 101.970, 74.110
Angle α, β, γ (deg.)90.000, 89.860, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein E3 ubiquitin-protein ligase CBL-B / Casitas B-lineage lymphoma proto-oncogene b / RING finger protein 56 / RING-type E3 ubiquitin ...Casitas B-lineage lymphoma proto-oncogene b / RING finger protein 56 / RING-type E3 ubiquitin transferase CBL-B / SH3-binding protein CBL-B / Signal transduction protein CBL-B


Mass: 45694.336 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CBLB, RNF56, Nbla00127 / Production host: Escherichia coli (E. coli)
References: UniProt: Q13191, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-A1EVY / 5-fluoranyl-3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-8-[[(3~{S})-3-methylpiperidin-1-yl]methyl]-1~{H}-quinolin-2-one


Mass: 499.622 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H34FN5O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 180 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 48.11 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 7.3
Details: 0.1 M HEPES pH 7.3, 7% w/v polyethylene glycol 6,000, 5% v/v (+/-)-2-Methyl-2,4-pentanediol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 26, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→59.96 Å / Num. obs: 20816 / % possible obs: 99 % / Redundancy: 3.2 % / Biso Wilson estimate: 12.15 Å2 / CC1/2: 0.988 / Rmerge(I) obs: 0.172 / Net I/σ(I): 7.2
Reflection shellResolution: 2.8→2.95 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.346 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 3045 / CC1/2: 0.964 / % possible all: 98

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.17.1_3660phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→59.95 Å / SU ML: 0.3418 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 30.2239
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.3094 1985 9.54 %
Rwork0.2846 18825 -
obs0.287 20810 99.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 15.48 Å2
Refinement stepCycle: LAST / Resolution: 2.8→59.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6224 0 79 180 6483
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00456456
X-RAY DIFFRACTIONf_angle_d0.87048724
X-RAY DIFFRACTIONf_chiral_restr0.0483924
X-RAY DIFFRACTIONf_plane_restr0.0051104
X-RAY DIFFRACTIONf_dihedral_angle_d25.54782444
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8-2.870.34651450.33931339X-RAY DIFFRACTION98.41
2.87-2.950.32511430.3081318X-RAY DIFFRACTION98.05
2.95-3.030.3311430.30761333X-RAY DIFFRACTION98.99
3.03-3.130.37461370.29511326X-RAY DIFFRACTION98.92
3.13-3.240.32221460.29911349X-RAY DIFFRACTION99.07
3.24-3.370.30341400.28421347X-RAY DIFFRACTION99.13
3.37-3.530.30341380.27981333X-RAY DIFFRACTION99.26
3.53-3.710.29731380.26861341X-RAY DIFFRACTION99.4
3.71-3.950.27161410.2571350X-RAY DIFFRACTION99.27
3.95-4.250.30681490.25981341X-RAY DIFFRACTION99.2
4.25-4.680.28561430.26561356X-RAY DIFFRACTION99.4
4.68-5.360.26431390.26971335X-RAY DIFFRACTION99.39
5.36-6.740.31141400.2971371X-RAY DIFFRACTION99.41
6.75-59.950.34821430.31031386X-RAY DIFFRACTION98.9
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)
10.5293807946990.0341782878246-0.1112094122651.013651750820.1084807279391.259837775770.04296771552390.005485204339030.01300121138940.00438384393201-0.0361880510505-0.1572817684340.07614571035310.0501007240163-0.01446538494210.1030286854160.016452346786-0.00851650544240.09946699793230.02985713858590.1385776783143.7429450821-10.8786194605-0.228435358581
20.4061608802180.114948041448-0.06370498482130.574053359316-0.1135754710890.875933147940.01223573922880.003749330622070.0307703356907-0.03007879338970.005945547906950.0477602734675-0.0553775551125-0.180841400515-0.01596295901370.125071346808-0.00139910628311-0.02566140351660.1090975672550.009177466761520.11432348731926.9240913958-2.2391331089336.8490901034
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain A
2X-RAY DIFFRACTION2chain B

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