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- PDB-8eyb: Crystal structure of PTP1B D181A/Q262A/C215A phosphatase domain w... -

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Basic information

Entry
Database: PDB / ID: 8eyb
TitleCrystal structure of PTP1B D181A/Q262A/C215A phosphatase domain with JAK2 activation loop phosphopeptide
Components
  • Tyrosine-protein kinase JAK2 activation loop phosphopeptide
  • Tyrosine-protein phosphatase non-receptor type 1
KeywordsSIGNALING PROTEIN / PTP1B / JAK/STAT / IRK
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / interleukin-12 receptor complex / activation of Janus kinase activity / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / positive regulation of MHC class II biosynthetic process / positive regulation of platelet aggregation / Interleukin-23 signaling / type 1 angiotensin receptor binding / positive regulation of T-helper 17 type immune response / positive regulation of platelet activation / acetylcholine receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / Signaling by Leptin / regulation of nitric oxide biosynthetic process / positive regulation of signaling receptor activity / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of epithelial cell apoptotic process / response to hydroperoxide / positive regulation of natural killer cell proliferation / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / axon regeneration / growth hormone receptor signaling pathway / peptide hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / regulation of hepatocyte growth factor receptor signaling pathway / extrinsic component of plasma membrane / PTK6 Down-Regulation / IFNG signaling activates MAPKs / Interleukin-20 family signaling / interleukin-6-mediated signaling pathway / peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity / positive regulation of receptor catabolic process / insulin receptor recycling / negative regulation of cell-cell adhesion / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / enzyme-linked receptor protein signaling pathway / negative regulation of PERK-mediated unfolded protein response / negative regulation of vascular endothelial growth factor receptor signaling pathway / regulation of intracellular protein transport / Prolactin receptor signaling / IRE1-mediated unfolded protein response / MAPK3 (ERK1) activation / response to amine / positive regulation of interleukin-17 production / negative regulation of DNA binding / positive regulation of nitric-oxide synthase biosynthetic process / cytoplasmic side of endoplasmic reticulum membrane / platelet-derived growth factor receptor-beta signaling pathway / sorting endosome / mitochondrial crista / positive regulation of IRE1-mediated unfolded protein response / MAPK1 (ERK2) activation / cell surface receptor signaling pathway via JAK-STAT / mesoderm development / regulation of type I interferon-mediated signaling pathway / positive regulation of SMAD protein signal transduction / platelet-derived growth factor receptor signaling pathway / regulation of endocytosis / non-membrane spanning protein tyrosine phosphatase activity / positive regulation of protein tyrosine kinase activity / peptidyl-tyrosine dephosphorylation / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of IFNA/IFNB signaling / regulation of signal transduction / cellular response to unfolded protein / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / Jak1 pleckstrin homology-like domain ...Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / Protein-tyrosine phosphatase, non-receptor type-1/2 / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / 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 / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / 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
Similarity search - Domain/homology
Tyrosine-protein kinase JAK2 / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.349 Å
AuthorsMorris, R. / Kershaw, N.J. / Babon, J.J.
Funding support Australia, 1items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia) Australia
CitationJournal: Commun Biol / Year: 2023
Title: Structure guided studies of the interaction between PTP1B and JAK.
Authors: Morris, R. / Keating, N. / Tan, C. / Chen, H. / Laktyushin, A. / Saiyed, T. / Liau, N.P.D. / Nicola, N.A. / Tiganis, T. / Kershaw, N.J. / Babon, J.J.
History
DepositionOct 26, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 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: Tyrosine-protein phosphatase non-receptor type 1
B: Tyrosine-protein phosphatase non-receptor type 1
D: Tyrosine-protein kinase JAK2 activation loop phosphopeptide
E: Tyrosine-protein kinase JAK2 activation loop phosphopeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,8776
Polymers72,6334
Non-polymers2442
Water2,126118
1
A: Tyrosine-protein phosphatase non-receptor type 1
D: Tyrosine-protein kinase JAK2 activation loop phosphopeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4383
Polymers36,3162
Non-polymers1221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-5 kcal/mol
Surface area12610 Å2
MethodPISA
2
B: Tyrosine-protein phosphatase non-receptor type 1
E: Tyrosine-protein kinase JAK2 activation loop phosphopeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4383
Polymers36,3162
Non-polymers1221
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint-7 kcal/mol
Surface area12940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)88.381, 88.381, 190.335
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number152
Space group name H-MP3121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11(chain A and (resid 3 through 24 or (resid 25...
21(chain B and (resid 3 or (resid 4 through 6...

NCS domain segments:

Ens-ID: 1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11METMETARGARG(chain A and (resid 3 through 24 or (resid 25...AA3 - 242 - 23
12HISHISHISHIS(chain A and (resid 3 through 24 or (resid 25...AA2524
13GLUGLUMETMET(chain A and (resid 3 through 24 or (resid 25...AA2 - 2821 - 281
14GLUGLUMETMET(chain A and (resid 3 through 24 or (resid 25...AA2 - 2821 - 281
15GLUGLUMETMET(chain A and (resid 3 through 24 or (resid 25...AA2 - 2821 - 281
16GLUGLUMETMET(chain A and (resid 3 through 24 or (resid 25...AA2 - 2821 - 281
21METMETMETMET(chain B and (resid 3 or (resid 4 through 6...BB32
22GLUGLUGLUGLU(chain B and (resid 3 or (resid 4 through 6...BB4 - 63 - 5
23GLUGLUGLUGLU(chain B and (resid 3 or (resid 4 through 6...BB2 - 2971 - 296
24GLUGLUGLUGLU(chain B and (resid 3 or (resid 4 through 6...BB2 - 2971 - 296
25GLUGLUGLUGLU(chain B and (resid 3 or (resid 4 through 6...BB2 - 2971 - 296
26GLUGLUGLUGLU(chain B and (resid 3 or (resid 4 through 6...BB2 - 2971 - 296

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Components

#1: Protein Tyrosine-protein phosphatase non-receptor type 1 / Protein-tyrosine phosphatase 1B / PTP-1B


Mass: 34311.141 Da / Num. of mol.: 2 / Mutation: D181A/Q262A/C215A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN1, PTP1B / Production host: Escherichia coli (E. coli) / References: UniProt: P18031, protein-tyrosine-phosphatase
#2: Protein/peptide Tyrosine-protein kinase JAK2 activation loop phosphopeptide / Janus kinase 2 / JAK-2


Mass: 2005.140 Da / Num. of mol.: 2 / Fragment: residues 1000-1015 of JAK2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#3: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H12NO3 / Feature type: SUBJECT OF INVESTIGATION / Comment: pH buffer*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 118 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.13 Å3/Da / Density % sol: 60.75 %
Crystal growTemperature: 281 K / Method: vapor diffusion, sitting drop
Details: 25% w/v PEG 3350, 0.2 M NaCl, 0.1 M Tris Cl (pH 8.5)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.95373 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 15, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95373 Å / Relative weight: 1
ReflectionResolution: 2.34→48.85 Å / Num. obs: 36591 / % possible obs: 99.63 % / Redundancy: 5.6 % / CC1/2: 0.99 / Net I/σ(I): 18.94
Reflection shellResolution: 2.34→2.43 Å / Num. unique obs: 3580 / CC1/2: 0.77

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Processing

Software
NameVersionClassification
PHENIX1.16_3549refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZRT

4zrt


Resolution: 2.349→48.846 Å / SU ML: 0.34 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 26.38 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2431 2005 5.48 %
Rwork0.2073 34586 -
obs0.2093 36591 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 117.87 Å2 / Biso mean: 59.3185 Å2 / Biso min: 23.86 Å2
Refinement stepCycle: final / Resolution: 2.349→48.846 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4633 0 40 118 4791
Biso mean--74.39 53.37 -
Num. residues----587
Refine LS restraints NCS
Ens-IDDom-IDAuth asym-IDNumberRefine-IDRmsType
11A2573X-RAY DIFFRACTION9.25TORSIONAL
12B2573X-RAY DIFFRACTION9.25TORSIONAL
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.3494-2.40810.32681410.3034240999
2.4081-2.47330.35641400.27722476100
2.4733-2.5460.30461400.26982418100
2.546-2.62820.33921430.26362444100
2.6282-2.72210.29081420.25512430100
2.7221-2.83110.28951450.24882449100
2.8311-2.95990.31731440.2562465100
2.9599-3.1160.29311410.2526242999
3.116-3.31120.30741450.24022457100
3.3112-3.56670.2581400.2092471100
3.5667-3.92550.20471390.18862480100
3.9255-4.49320.19251460.17492505100
4.4932-5.65960.20971430.1721252899
5.6596-48.8460.2171560.1878262599

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