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- PDB-5hky: Crystal structure of c-Cbl TKBD domain in complex with SPRY2 pept... -

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Basic information

Entry
Database: PDB / ID: 5hky
TitleCrystal structure of c-Cbl TKBD domain in complex with SPRY2 peptide (36-60, pY55) Refined to 1.8A Resolution (P6 form)
Components
  • E3 ubiquitin-protein ligase CBL
  • Protein sprouty homolog 2
KeywordsLIGASE / SPRY2 / Cbl / Protein-protein interaction / anticancer target
Function / homology
Function and homology information


microtubule end / lung growth / negative regulation of lens fiber cell differentiation / negative regulation of cell projection organization / ubiquitin-protein transferase inhibitor activity / negative regulation of neurotrophin TRK receptor signaling pathway / regulation of platelet-derived growth factor receptor-alpha signaling pathway / ubiquitin-dependent endocytosis / animal organ development / negative regulation of fibroblast growth factor receptor signaling pathway ...microtubule end / lung growth / negative regulation of lens fiber cell differentiation / negative regulation of cell projection organization / ubiquitin-protein transferase inhibitor activity / negative regulation of neurotrophin TRK receptor signaling pathway / regulation of platelet-derived growth factor receptor-alpha signaling pathway / ubiquitin-dependent endocytosis / animal organ development / negative regulation of fibroblast growth factor receptor signaling pathway / negative regulation of vascular endothelial growth factor signaling pathway / regulation of Rap protein signal transduction / bud elongation involved in lung branching / entry of bacterium into host cell / negative regulation of epithelial to mesenchymal transition / flotillin complex / phosphatidylinositol 3-kinase regulatory subunit binding / negative regulation of Ras protein signal transduction / protein serine/threonine kinase inhibitor activity / positive regulation of epidermal growth factor receptor signaling pathway / inner ear morphogenesis / Regulation of KIT signaling / mast cell degranulation / response to testosterone / Interleukin-6 signaling / negative regulation of epidermal growth factor receptor signaling pathway / response to starvation / cellular response to platelet-derived growth factor stimulus / negative regulation of peptidyl-threonine phosphorylation / protein monoubiquitination / TGF-beta receptor signaling activates SMADs / establishment of mitotic spindle orientation / fibroblast growth factor receptor signaling pathway / cellular response to vascular endothelial growth factor stimulus / cell fate commitment / protein autoubiquitination / negative regulation of protein ubiquitination / FLT3 signaling by CBL mutants / ERK1 and ERK2 cascade / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / cellular response to leukemia inhibitory factor / phosphotyrosine residue binding / ephrin receptor binding / protein serine/threonine kinase activator activity / negative regulation of angiogenesis / cellular response to nerve growth factor stimulus / InlB-mediated entry of Listeria monocytogenes into host cell / response to activity / Regulation of signaling by CBL / Negative regulation of FGFR3 signaling / response to gamma radiation / sensory perception of sound / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / EGFR downregulation / Negative regulation of FGFR1 signaling / negative regulation of transforming growth factor beta receptor signaling pathway / Spry regulation of FGF signaling / RING-type E3 ubiquitin transferase / Constitutive Signaling by EGFRvIII / cilium / Negative regulation of MET activity / negative regulation of ERK1 and ERK2 cascade / receptor tyrosine kinase binding / ruffle membrane / SH3 domain binding / protein polyubiquitination / positive regulation of receptor-mediated endocytosis / cytokine-mediated signaling pathway / ubiquitin-protein transferase activity / male gonad development / Signaling by CSF1 (M-CSF) in myeloid cells / ubiquitin protein ligase activity / microtubule cytoskeleton / actin cytoskeleton / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / positive regulation of peptidyl-serine phosphorylation / growth cone / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / response to ethanol / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein ubiquitination / cytoskeleton / positive regulation of cell migration / cadherin binding / membrane raft / negative regulation of cell population proliferation / focal adhesion / DNA damage response / calcium ion binding / positive regulation of gene expression / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / Golgi apparatus
Similarity search - Function
Sprouty / Sprouty protein (Spry) / Sprouty (SPR) domain profile. / Adaptor protein Cbl, N-terminal domain / 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 ...Sprouty / Sprouty protein (Spry) / Sprouty (SPR) domain profile. / Adaptor protein Cbl, N-terminal domain / 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 / Transcription Elongation Factor S-II; Chain A / UBA/TS-N domain / Ubiquitin associated domain / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / UBA-like superfamily / SH2 domain / SHC Adaptor Protein / EF-hand / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Recoverin; domain 1 / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / SH2 domain superfamily / EF-hand domain pair / Zinc finger, RING/FYVE/PHD-type / Up-down Bundle / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Protein sprouty homolog 2 / E3 ubiquitin-protein ligase CBL
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 Å
AuthorsLovell, S. / Battaile, K.P. / Mehzabeen, N. / Zhang, N. / Cooper, A. / Gao, P. / Perez, R.P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5P20RR017708-10 / 8P20GM103420-10 United States
CitationJournal: To be published
Title: Crystal structure of c-Cbl TKBD domain in complex with SPRY2 peptide (36-60, pY55) Refined to 1.8A Resolution (P6 form)
Authors: Zhang, N. / Ferris, D. / Lovell, S. / Smalter-Hall, A. / Battaile, K.P. / Anbanandam, A. / Gao, P. / Hanzlik, R. / Perez, R.P.
History
DepositionJan 14, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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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: Protein sprouty homolog 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0276
Polymers38,6942
Non-polymers3324
Water5,080282
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2960 Å2
ΔGint-47 kcal/mol
Surface area15030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)122.810, 122.810, 58.440
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number168
Space group name H-MP6
Components on special symmetry positions
IDModelComponents
11A-728-

HOH

21B-121-

HOH

31B-122-

HOH

41B-124-

HOH

51B-125-

HOH

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein E3 ubiquitin-protein ligase CBL / Casitas B-lineage lymphoma proto-oncogene / Proto-oncogene c-Cbl / RING finger protein 55 / Signal ...Casitas B-lineage lymphoma proto-oncogene / Proto-oncogene c-Cbl / RING finger protein 55 / Signal transduction protein CBL


Mass: 35702.219 Da / Num. of mol.: 1
Fragment: Tyrosine kinase binding domain (TKBD), residues 47-351
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CBL, CBL2, RNF55 / Plasmid: pTBSG / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) pLyseS-RARE
References: UniProt: P22681, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Protein/peptide Protein sprouty homolog 2 / Spry-2


Mass: 2992.173 Da / Num. of mol.: 1 / Fragment: unp residues 36-60 / Source method: obtained synthetically
Details: Synthesized by New England Peptide with an acetylated N-terminus
Source: (synth.) Homo sapiens (human) / References: UniProt: O43597

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Non-polymers , 4 types, 286 molecules

#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400 / Polyethylene glycol


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 282 / Source method: isolated from a natural source / Formula: H2O

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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: 3.29 Å3/Da / Density % sol: 62.59 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 30% (v/v) PEG 400, 0.1M HEPES, 200 mM MgCl2

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 17, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→42.33 Å / Num. obs: 46770 / % possible obs: 100 % / Redundancy: 10.1 % / Biso Wilson estimate: 22.19 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.111 / Net I/σ(I): 14.8 / Num. measured all: 474170 / Scaling rejects: 2
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2% possible all
1.8-1.84101.2262.22798227950.718100
9-42.339.90.04146.240164050.99998.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.2.17data scaling
PHASER2.5.6phasing
PHENIXrefinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BUM

3bum


Resolution: 1.8→40.199 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.05 / Phase error: 17.19 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1801 2258 4.83 %
Rwork0.1569 44506 -
obs0.158 46764 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 84.45 Å2 / Biso mean: 27.744 Å2 / Biso min: 9.78 Å2
Refinement stepCycle: final / Resolution: 1.8→40.199 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2604 0 17 282 2903
Biso mean--37.63 35.75 -
Num. residues----325
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012734
X-RAY DIFFRACTIONf_angle_d1.033715
X-RAY DIFFRACTIONf_chiral_restr0.048408
X-RAY DIFFRACTIONf_plane_restr0.007470
X-RAY DIFFRACTIONf_dihedral_angle_d15.8081018
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 16 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
1.8001-1.83920.25191130.243928222935
1.8392-1.8820.27881250.217327642889
1.882-1.92910.20961230.197827582881
1.9291-1.98120.20651760.179227312907
1.9812-2.03950.19891590.167427692928
2.0395-2.10530.2121470.163227352882
2.1053-2.18060.19991330.155927712904
2.1806-2.26790.17751300.152327932923
2.2679-2.37110.17411550.149827492904
2.3711-2.49610.16831520.145527582910
2.4961-2.65240.19791200.150528122932
2.6524-2.85720.17311370.159327822919
2.8572-3.14460.18631490.165727952944
3.1446-3.59940.18881450.153327792924
3.5994-4.53390.15261410.130628242965
4.5339-40.2090.1551530.156128643017

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