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- PDB-10zf: Structure of c-Cbl bound to compound 33 -

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Basic information

Entry
Database: PDB / ID: 10zf
TitleStructure of c-Cbl bound to compound 33
ComponentsGlutathione S-transferase class-mu 26 kDa isozyme,E3 ubiquitin-protein ligase CBL
KeywordsLIGASE / Ubiquitin ligase / E3 / inhibitor
Function / homology
Function and homology information


regulation of platelet-derived growth factor receptor-alpha signaling pathway / regulation of Rap protein signal transduction / flotillin complex / phosphatidylinositol 3-kinase regulatory subunit binding / Regulation of KIT signaling / ubiquitin-dependent endocytosis / Interleukin-6 signaling / response to starvation / mast cell degranulation / negative regulation of T cell activation ...regulation of platelet-derived growth factor receptor-alpha signaling pathway / regulation of Rap protein signal transduction / flotillin complex / phosphatidylinositol 3-kinase regulatory subunit binding / Regulation of KIT signaling / ubiquitin-dependent endocytosis / Interleukin-6 signaling / response to starvation / mast cell degranulation / negative regulation of T cell activation / response to testosterone / TGF-beta receptor signaling activates SMADs / glutathione transferase / negative regulation of epidermal growth factor receptor signaling pathway / glutathione transferase activity / negative regulation of T cell receptor signaling pathway / protein K63-linked ubiquitination / protein monoubiquitination / positive regulation of epidermal growth factor receptor signaling pathway / protein autoubiquitination / ephrin receptor binding / cellular response to platelet-derived growth factor stimulus / phosphotyrosine residue binding / FLT3 signaling by CBL mutants / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / response to activity / InlB-mediated entry of Listeria monocytogenes into host cell / response to gamma radiation / glutathione metabolic process / Regulation of signaling by CBL / sperm end piece / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / EGFR downregulation / cellular response to nerve growth factor stimulus / Constitutive Signaling by EGFRvIII / Spry regulation of FGF signaling / Negative regulation of MET activity / SH3 domain binding / positive regulation of receptor-mediated endocytosis / receptor tyrosine kinase binding / RING-type E3 ubiquitin transferase / male gonad development / cytokine-mediated signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / ubiquitin-protein transferase activity / ubiquitin protein ligase activity / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / growth cone / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / response to ethanol / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein stabilization / cilium / protein ubiquitination / cadherin binding / membrane raft / focal adhesion / calcium ion binding / DNA damage response / symbiont entry into host cell / negative regulation of apoptotic process / perinuclear region of cytoplasm / Golgi apparatus / signal transduction / zinc ion binding / plasma membrane / cytosol
Similarity search - Function
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 ...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 / UBA/TS-N domain / Glutathione S-transferase, C-terminal domain / Ubiquitin associated domain / : / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / UBA-like superfamily / Glutathione S-transferase, N-terminal domain / Glutathione S-transferase, C-terminal / Glutathione transferase family / Glutathione S-transferase, C-terminal-like / Soluble glutathione S-transferase C-terminal domain profile. / Soluble glutathione S-transferase N-terminal domain profile. / Glutathione S-transferase, N-terminal / Glutathione S-transferase, C-terminal domain superfamily / 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 / Thioredoxin-like superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
: / Glutathione S-transferase class-mu 26 kDa isozyme / E3 ubiquitin-protein ligase CBL
Similarity search - Component
Biological speciesSchistosoma japonicum (invertebrata)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.39 Å
AuthorsMurray, J. / Yu, C. / Hsu, P.L.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2026
Title: Optimization Leading to a Potent and Selective Cbl‐b Inactive-State Inhibitor That Demonstrated In Vivo Efficacy.
Authors: Liang, J. / Lambrecht, M.J. / Huestis, M.P. / Zhu, B. / Barton, L.M. / Castanedo, G.M. / Ung, P.M. / Larouche-Gauthier, R. / Jakalian, A. / Leclerc, J.P. / Yadav, A. / Haghshenas, P. / ...Authors: Liang, J. / Lambrecht, M.J. / Huestis, M.P. / Zhu, B. / Barton, L.M. / Castanedo, G.M. / Ung, P.M. / Larouche-Gauthier, R. / Jakalian, A. / Leclerc, J.P. / Yadav, A. / Haghshenas, P. / Aubert-Nicol, S. / Ismaili, H. / Zhao, L. / Leblanc, M. / de Almeida, H. / Wang, Q. / Garner, T. / Tan, S. / Prangley, M.S. / Pang, J. / Murray, J.M. / Yu, C. / Hsu, P.L. / Rutz, S. / Ishizuka, I. / Huang, H. / Gao, C. / Chen, M. / Mutter-Rottmayer, L. / Kakiuchi-Kiyota, S. / Leung, D.H. / Kou, P. / Bao, L. / Wang, X.
History
DepositionFeb 12, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 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: Glutathione S-transferase class-mu 26 kDa isozyme,E3 ubiquitin-protein ligase CBL
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,4835
Polymers72,7881
Non-polymers6954
Water1,26170
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)101.720, 49.860, 83.872
Angle α, β, γ (deg.)90.00, 92.06, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Glutathione S-transferase class-mu 26 kDa isozyme,E3 ubiquitin-protein ligase CBL


Mass: 72787.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Schistosoma japonicum (invertebrata), (gene. exp.) Homo sapiens (human)
Gene: CBL, CBL2, RNF55 / Production host: Escherichia coli (E. coli)
References: UniProt: P08515, UniProt: P22681, glutathione transferase, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-A1DCD / 2-{3-[(1r,3r)-3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]phenyl}-6-{[(1-methylcyclobutyl)amino]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one


Mass: 539.592 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H32F3N5O2 / 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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 70 / 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

Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2M NaCH3COO, 0.1M Tris pH8.5, 16% PEG4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Jan 27, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.39→30.35 Å / Num. obs: 11608 / % possible obs: 88.5 % / Redundancy: 3.4 % / CC1/2: 0.99 / Rmerge(I) obs: 0.12 / Net I/σ(I): 6.2
Reflection shellResolution: 2.39→2.63 Å / Mean I/σ(I) obs: 1.5 / Num. unique obs: 699 / CC1/2: 0.58

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
XDSdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.39→30.35 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 29.27 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2561 605 5.21 %
Rwork0.1981 --
obs0.2011 11608 68.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.39→30.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3153 0 42 70 3265
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0023290
X-RAY DIFFRACTIONf_angle_d0.4654460
X-RAY DIFFRACTIONf_dihedral_angle_d14.0781267
X-RAY DIFFRACTIONf_chiral_restr0.038472
X-RAY DIFFRACTIONf_plane_restr0.004567
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID
2.39-2.630.4021400.2832659X-RAY DIFFRACTION
2.63-3.010.35651520.29572476X-RAY DIFFRACTION
3.01-3.780.27342120.2183837X-RAY DIFFRACTION
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)
12.8554-0.04810.04751.55420.99653.08410.21420.2776-0.4479-0.2790.0934-0.09550.95260.084-0.20470.70550.1226-0.12070.5238-0.23290.6588-9.8701-5.434510.6743
23.36540.68440.28442.34370.91773.85140.18390.696-0.6746-0.26850.0041-0.32930.1490.3228-0.19220.39810.01710.09130.3641-0.13180.3576-11.93590.375212.5182
31.6127-0.1146-0.23240.923-0.72483.69780.02570.11490.0405-0.1325-0.122-0.0562-0.03570.15120.06010.23440.0001-0.04520.1705-0.00620.2182-18.711213.49727.8168
42.0447-0.67150.73292.11280.97881.9809-0.0874-0.2460.34390.5358-0.324-0.2263-0.3994-0.05530.38520.297-0.0602-0.0540.2516-0.00030.2964-18.265319.149643.954
53.62522.08770.14735.7738-2.35051.4118-0.25170.4406-0.4358-1.04490.1435-0.84810.1850.95170.10680.4023-0.06390.10570.4889-0.04650.5248-1.473616.638826.7225
60.59070.4366-0.25044.2419-0.36042.26990.0032-0.3489-0.1297-0.5322-0.3507-0.955-0.21711.4020.46570.8562-0.3730.10971.58770.36181.42519.047422.933917.6938
72.3126-0.0001-0.31050.053-0.36482.51830.1761-0.5059-0.84690.08260.08980.41810.47740.5426-0.10991.099-0.2790.1111.32420.22391.793611.74422.83519.7713
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 47 through 83 )
2X-RAY DIFFRACTION2chain 'A' and (resid 84 through 168 )
3X-RAY DIFFRACTION3chain 'A' and (resid 169 through 323 )
4X-RAY DIFFRACTION4chain 'A' and (resid 324 through 364 )
5X-RAY DIFFRACTION5chain 'A' and (resid 365 through 384 )
6X-RAY DIFFRACTION6chain 'A' and (resid 385 through 409 )
7X-RAY DIFFRACTION7chain 'A' and (resid 410 through 435 )

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