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- PDB-4nnd: Structural basis of PTPN18 fingerprint on distinct HER2 tyrosine ... -

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Basic information

Entry
Database: PDB / ID: 4nnd
TitleStructural basis of PTPN18 fingerprint on distinct HER2 tyrosine phosphorylation sites
Components
  • Receptor tyrosine-protein kinase erbB-2
  • Tyrosine-protein phosphatase non-receptor type 18
KeywordsHYDROLASE / beta barrel / beta-propeller / kinase binding / phosphorylation
Function / homology
Function and homology information


negative regulation of ERBB signaling pathway / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / blastocyst formation / regulation of microtubule-based process ...negative regulation of ERBB signaling pathway / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / semaphorin receptor complex / blastocyst formation / regulation of microtubule-based process / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / Interleukin-37 signaling / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / positive regulation of Rho protein signal transduction / ERBB2-EGFR signaling pathway / neuromuscular junction development / ERBB2 Activates PTK6 Signaling / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / enzyme-linked receptor protein signaling pathway / positive regulation of transcription by RNA polymerase I / ERBB2-ERBB3 signaling pathway / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / positive regulation of protein targeting to membrane / non-membrane spanning protein tyrosine phosphatase activity / positive regulation of cell adhesion / regulation of angiogenesis / coreceptor activity / Schwann cell development / Signaling by ERBB2 / cellular response to epidermal growth factor stimulus / myelination / Downregulation of ERBB2:ERBB3 signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / neurogenesis / SHC1 events in ERBB2 signaling / Constitutive Signaling by Overexpressed ERBB2 / protein dephosphorylation / basal plasma membrane / regulation of ERK1 and ERK2 cascade / protein-tyrosine-phosphatase / positive regulation of translation / phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein tyrosine phosphatase activity / positive regulation of epithelial cell proliferation / Signaling by ERBB2 TMD/JMD mutants / neuromuscular junction / positive regulation of MAP kinase activity / wound healing / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / receptor tyrosine kinase binding / receptor protein-tyrosine kinase / neuron differentiation / cellular response to growth factor stimulus / ruffle membrane / Downregulation of ERBB2 signaling / peptidyl-tyrosine phosphorylation / cell surface receptor protein tyrosine kinase signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / transmembrane signaling receptor activity / PIP3 activates AKT signaling / presynaptic membrane / myelin sheath / heart development / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase cascade / positive regulation of cell growth / basolateral plasma membrane / protein tyrosine kinase activity / positive regulation of MAPK cascade / cell surface receptor signaling pathway / receptor complex / early endosome / endosome membrane / intracellular signal transduction / positive regulation of protein phosphorylation / apical plasma membrane / protein heterodimerization activity / signaling receptor binding / protein phosphorylation / positive regulation of cell population proliferation / negative regulation of apoptotic process / perinuclear region of cytoplasm
Similarity search - Function
: / : / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily ...: / : / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Protein tyrosine phosphatase superfamily / Furin-like repeat / Furin-like repeats / Protein-Tyrosine Phosphatase; Chain A / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Protein-tyrosine phosphatase / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase, catalytic / Protein tyrosine phosphatase, catalytic domain motif / Tyrosine specific protein phosphatases active site. / Protein-tyrosine phosphatase, active site / Tyrosine-specific protein phosphatases domain / Tyrosine specific protein phosphatases domain profile. / Protein-tyrosine phosphatase-like / Growth factor receptor cysteine-rich domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2 / Tyrosine-protein phosphatase non-receptor type 18
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.502 Å
AuthorsWang, H. / Yang, F. / Yang, D. / Du, Y.
Citation
Journal: To be Published
Title: Structural basis of PTPN18 fingerprint on distinct HER2 tyrosine phosphorylation sites
Authors: Wang, H. / Yang, F. / Yang, D. / Du, Y.
#1: Journal: Cell(Cambridge,Mass.) / Year: 2009
Title: Large-scale structural analysis of the classical human protein tyrosine phosphatome.
Authors: Barr, A.J. / Ugochukwu, E. / Lee, W.H. / King, O.N. / Filippakopoulos, P. / Alfano, I. / Savitsky, P. / Burgess-Brown, N.A. / Muller, S. / Knapp, S.
History
DepositionNov 17, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 19, 2014Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein phosphatase non-receptor type 18
F: Receptor tyrosine-protein kinase erbB-2
B: Tyrosine-protein phosphatase non-receptor type 18
C: Receptor tyrosine-protein kinase erbB-2
D: Tyrosine-protein phosphatase non-receptor type 18
E: Receptor tyrosine-protein kinase erbB-2
G: Tyrosine-protein phosphatase non-receptor type 18
H: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)135,8158
Polymers135,8158
Non-polymers00
Water1,33374
1
A: Tyrosine-protein phosphatase non-receptor type 18
F: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)33,9542
Polymers33,9542
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1000 Å2
ΔGint-6 kcal/mol
Surface area13060 Å2
MethodPISA
2
B: Tyrosine-protein phosphatase non-receptor type 18
C: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)33,9542
Polymers33,9542
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area990 Å2
ΔGint-6 kcal/mol
Surface area13180 Å2
MethodPISA
3
D: Tyrosine-protein phosphatase non-receptor type 18
E: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)33,9542
Polymers33,9542
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area830 Å2
ΔGint-5 kcal/mol
Surface area12810 Å2
MethodPISA
4
G: Tyrosine-protein phosphatase non-receptor type 18
H: Receptor tyrosine-protein kinase erbB-2


Theoretical massNumber of molelcules
Total (without water)33,9542
Polymers33,9542
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area940 Å2
ΔGint-6 kcal/mol
Surface area12660 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.102, 95.284, 88.161
Angle α, β, γ (deg.)90.00, 94.02, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-ID
11
21
31
41

NCS domain segments:
Dom-IDComponent-IDEns-IDSelection details
111chain A and (resseq 25:294 )
211chain B and (resseq 25:294 )
311chain D and (resseq 25:294 )
411chain G and (resseq 25:294 )

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Components

#1: Protein
Tyrosine-protein phosphatase non-receptor type 18 / Brain-derived phosphatase


Mass: 33077.863 Da / Num. of mol.: 4
Fragment: tyrosine-protein phosphatase domain (UNP residues 6-295)
Mutation: C229S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN18, BDP1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q99952, protein-tyrosine-phosphatase
#2: Protein/peptide
Receptor tyrosine-protein kinase erbB-2 / Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / ...Metastatic lymph node gene 19 protein / MLN 19 / Proto-oncogene Neu / Proto-oncogene c-ErbB-2 / Tyrosine kinase-type cell surface receptor HER2 / p185erbB2


Mass: 875.840 Da / Num. of mol.: 4 / Fragment: phosphorylated peptide (UNP residues 1109-1114) / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P04626
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 74 / 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: 2.29 Å3/Da / Density % sol: 46.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: 0.1 M HEPES, 25% PEG3350, 6% Jeffamine M-600, pH 6.8, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 293 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.502→35 Å / Num. all: 44318 / Num. obs: 40329 / % possible obs: 91 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1
Reflection shell
Resolution (Å)Diffraction-ID% possible all
2.502-2.59195.5
2.59-2.69196.2
2.69-2.82195.5
2.82-2.96195.7
2.96-3.15196.6
3.15-3.39198.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHENIX(phenix.refine: 1.6.2_432)model building
PHENIX(phenix.refine: 1.6.2_432)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIX1.6.2_432phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.502→34.959 Å / SU ML: 0.3 / σ(F): 0 / Phase error: 46.41 / Stereochemistry target values: MLHL
RfactorNum. reflection% reflection
Rfree0.2907 1966 5.08 %
Rwork0.2623 --
obs0.2638 38726 91.46 %
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 37.231 Å2 / ksol: 0.384 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--5.3721 Å20 Å22.225 Å2
2--11.4683 Å20 Å2
3----6.0962 Å2
Refinement stepCycle: LAST / Resolution: 2.502→34.959 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9256 0 0 74 9330
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.019401
X-RAY DIFFRACTIONf_angle_d1.30712718
X-RAY DIFFRACTIONf_dihedral_angle_d16.7223510
X-RAY DIFFRACTIONf_chiral_restr0.0861380
X-RAY DIFFRACTIONf_plane_restr0.0051640
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDTypeRms dev position (Å)
11A2160X-RAY DIFFRACTIONPOSITIONAL
12B2160X-RAY DIFFRACTIONPOSITIONAL0.031
13D2151X-RAY DIFFRACTIONPOSITIONAL0.066
14G2117X-RAY DIFFRACTIONPOSITIONAL0.068
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.502-2.5910.37511630.2953501X-RAY DIFFRACTION86
2.591-2.69470.34031980.28983602X-RAY DIFFRACTION91
2.6947-2.81730.34931990.28423550X-RAY DIFFRACTION89
2.8173-2.96580.34572120.27793573X-RAY DIFFRACTION90
2.9658-3.15150.32521950.26853684X-RAY DIFFRACTION92
3.1515-3.39460.28862040.26883805X-RAY DIFFRACTION95
3.3946-3.73590.282110.2633841X-RAY DIFFRACTION96
3.7359-4.27560.25692010.24783734X-RAY DIFFRACTION93
4.2756-5.38370.2512010.22173828X-RAY DIFFRACTION95
5.3837-34.96260.27011820.27933642X-RAY DIFFRACTION88

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