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- PDB-5hkz: Crystal Structure of c-Cbl TKBD in complex with SPRY2 peptide (36... -

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Basic information

Entry
Database: PDB / ID: 5hkz
TitleCrystal Structure of c-Cbl TKBD in complex with SPRY2 peptide (36-60, pY55) Refined to 1.8 A Resolution (P21 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 / negative regulation of lens fiber cell differentiation / negative regulation of cell projection organization / lung growth / negative regulation of neurotrophin TRK receptor signaling pathway / regulation of platelet-derived growth factor receptor-alpha signaling pathway / negative regulation of vascular endothelial growth factor signaling pathway / negative regulation of fibroblast growth factor receptor signaling pathway / ubiquitin-dependent endocytosis / regulation of Rap protein signal transduction ...microtubule end / negative regulation of lens fiber cell differentiation / negative regulation of cell projection organization / lung growth / negative regulation of neurotrophin TRK receptor signaling pathway / regulation of platelet-derived growth factor receptor-alpha signaling pathway / negative regulation of vascular endothelial growth factor signaling pathway / negative regulation of fibroblast growth factor receptor signaling pathway / ubiquitin-dependent endocytosis / regulation of Rap protein signal transduction / animal organ development / ubiquitin-protein transferase inhibitor activity / bud elongation involved in lung branching / flotillin complex / phosphatidylinositol 3-kinase regulatory subunit binding / negative regulation of Ras protein signal transduction / positive regulation of epidermal growth factor receptor signaling pathway / Regulation of KIT signaling / negative regulation of epithelial to mesenchymal transition / inner ear morphogenesis / Interleukin-6 signaling / mast cell degranulation / response to starvation / response to testosterone / negative regulation of epidermal growth factor receptor signaling pathway / TGF-beta receptor signaling activates SMADs / establishment of mitotic spindle orientation / cellular response to vascular endothelial growth factor stimulus / fibroblast growth factor receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / protein monoubiquitination / cell fate commitment / protein serine/threonine kinase inhibitor activity / protein autoubiquitination / ephrin receptor binding / cellular response to platelet-derived growth factor stimulus / ERK1 and ERK2 cascade / phosphotyrosine residue binding / FLT3 signaling by CBL mutants / negative regulation of protein ubiquitination / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / negative regulation of angiogenesis / InlB-mediated entry of Listeria monocytogenes into host cell / protein serine/threonine kinase activator activity / cellular response to leukemia inhibitory factor / response to activity / response to gamma radiation / Regulation of signaling by CBL / Negative regulation of FGFR3 signaling / negative regulation of transforming growth factor beta receptor signaling pathway / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / EGFR downregulation / sensory perception of sound / Spry regulation of FGF signaling / Constitutive Signaling by EGFRvIII / cellular response to nerve growth factor stimulus / Negative regulation of MET activity / RING-type E3 ubiquitin transferase / receptor tyrosine kinase binding / negative regulation of ERK1 and ERK2 cascade / positive regulation of receptor-mediated endocytosis / SH3 domain binding / male gonad development / ruffle membrane / cytokine-mediated signaling pathway / protein polyubiquitination / Signaling by CSF1 (M-CSF) in myeloid cells / ubiquitin-protein transferase activity / ubiquitin protein ligase activity / Cargo recognition for clathrin-mediated endocytosis / actin cytoskeleton / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / microtubule cytoskeleton / growth cone / response to ethanol / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / cytoskeleton / positive regulation of ERK1 and ERK2 cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cilium / positive regulation of cell migration / protein ubiquitination / cadherin binding / membrane raft / negative regulation of cell population proliferation / focal adhesion / calcium ion binding / DNA damage response / positive regulation of gene expression / symbiont entry into host cell / protein kinase binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / Golgi apparatus / signal transduction
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 ...: / 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 / Ubiquitin-associated domain / Ubiquitin-associated domain (UBA) profile. / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / SH2 domain / SHC Adaptor Protein / UBA-like superfamily / 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 in complex with SPRY2 peptide (36-60, pY55) Refined to 1.8 A Resolution (P21 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
Revision 1.5Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)38,7173
Polymers38,6942
Non-polymers231
Water3,711206
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2400 Å2
ΔGint-29 kcal/mol
Surface area15030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.164, 56.572, 58.228
Angle α, β, γ (deg.)90.000, 107.150, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#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
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 206 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.04 Å3/Da / Density % sol: 39.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: 25% (w/v) PEG 2000 MME, 0.1M HEPES

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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→43.15 Å / Num. obs: 28815 / % possible obs: 99.4 % / Redundancy: 3.3 % / Biso Wilson estimate: 22.55 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.054 / Net I/σ(I): 16.3 / Num. measured all: 95633 / Scaling rejects: 2
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allCC1/2% possible all
1.8-1.843.20.6651.9543616730.65299.4
9-43.153.30.01858.18162500.99997.1

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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→39.668 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.08 / Phase error: 21.28 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2126 1401 4.86 %
Rwork0.1618 27397 -
obs0.1642 28798 99.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 70.55 Å2 / Biso mean: 25.0576 Å2 / Biso min: 9.7 Å2
Refinement stepCycle: final / Resolution: 1.8→39.668 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2574 0 1 206 2781
Biso mean--17.24 32.21 -
Num. residues----328
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012659
X-RAY DIFFRACTIONf_angle_d0.9963620
X-RAY DIFFRACTIONf_chiral_restr0.052403
X-RAY DIFFRACTIONf_plane_restr0.006459
X-RAY DIFFRACTIONf_dihedral_angle_d14.74956
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8001-1.86440.3111230.24772707283099
1.8644-1.93910.26351580.22762733289199
1.9391-2.02730.27371360.18842694283099
2.0273-2.13420.26451230.16982750287399
2.1342-2.26790.22881520.164327212873100
2.2679-2.4430.22211560.156227402896100
2.443-2.68880.22941500.153127462896100
2.6888-3.07770.22481270.156827532880100
3.0777-3.87710.17471490.14652747289699
3.8771-39.67770.17621270.15272806293398

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