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- PDB-6e2q: Structure of human JAK2 FERM/SH2 in complex with Erythropoietin R... -

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Basic information

Entry
Database: PDB / ID: 6e2q
TitleStructure of human JAK2 FERM/SH2 in complex with Erythropoietin Receptor
Components
  • Erythropoietin receptor
  • Tyrosine-protein kinase JAK2
KeywordsSIGNALING PROTEIN / Cytokine Receptor / Erythropoietin / Signal Transduction
Function / homology
Function and homology information


erythropoietin receptor activity / interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor 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 ...erythropoietin receptor activity / interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor 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 / interleukin-12 receptor binding / post-embryonic hemopoiesis / collagen-activated signaling pathway / Erythropoietin activates STAT5 / Erythropoietin activates Phospholipase C gamma (PLCG) / interleukin-5-mediated signaling pathway / response to interleukin-12 / positive regulation of leukocyte proliferation / activation of Janus kinase activity / interleukin-12 receptor complex / interleukin-23 receptor complex / positive regulation of platelet aggregation / tyrosine phosphorylation of STAT protein / positive regulation of platelet activation / positive regulation of MHC class II biosynthetic process / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / acetylcholine receptor binding / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / cellular response to interleukin-3 / Signaling by Leptin / positive regulation of signaling receptor activity / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / positive regulation of cell-substrate adhesion / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / positive regulation of epithelial cell apoptotic process / axon regeneration / peptide hormone receptor binding / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / IFNG signaling activates MAPKs / Interleukin-20 family signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / negative regulation of cell-cell adhesion / Prolactin receptor signaling / positive regulation of interleukin-17 production / negative regulation of DNA binding / MAPK3 (ERK1) activation / response to amine / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / mesoderm development / positive regulation of natural killer cell proliferation / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / hemopoiesis / platelet-derived growth factor receptor signaling pathway / decidualization / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / positive regulation of apoptotic signaling pathway / extrinsic apoptotic signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / extrinsic component of cytoplasmic side of plasma membrane / SH2 domain binding / cellular response to dexamethasone stimulus / post-translational protein modification / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production
Similarity search - Function
Erythropoietin receptor / Long hematopoietin receptor, single chain, conserved site / Long hematopoietin receptor, single chain family signature. / Growth hormone/erythropoietin receptor, ligand binding / Erythropoietin receptor, ligand binding / 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 ...Erythropoietin receptor / Long hematopoietin receptor, single chain, conserved site / Long hematopoietin receptor, single chain family signature. / Growth hormone/erythropoietin receptor, ligand binding / Erythropoietin receptor, ligand binding / 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 / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / 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. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Tyrosine-protein kinase JAK2 / Erythropoietin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.65 Å
AuthorsFerrao, R. / Lupardus, P.J.
CitationJournal: Elife / Year: 2018
Title: Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation.
Authors: Ferrao, R.D. / Wallweber, H. / Lupardus, P.J.
History
DepositionJul 11, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
B: Tyrosine-protein kinase JAK2
C: Tyrosine-protein kinase JAK2
D: Tyrosine-protein kinase JAK2
M: Erythropoietin receptor
N: Erythropoietin receptor
O: Erythropoietin receptor
P: Erythropoietin receptor


Theoretical massNumber of molelcules
Total (without water)258,9778
Polymers258,9778
Non-polymers00
Water2,612145
1
A: Tyrosine-protein kinase JAK2
N: Erythropoietin receptor


Theoretical massNumber of molelcules
Total (without water)64,7442
Polymers64,7442
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3960 Å2
ΔGint-29 kcal/mol
Surface area25530 Å2
MethodPISA
2
B: Tyrosine-protein kinase JAK2
O: Erythropoietin receptor


Theoretical massNumber of molelcules
Total (without water)64,7442
Polymers64,7442
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3940 Å2
ΔGint-29 kcal/mol
Surface area25010 Å2
MethodPISA
3
C: Tyrosine-protein kinase JAK2
M: Erythropoietin receptor


Theoretical massNumber of molelcules
Total (without water)64,7442
Polymers64,7442
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2790 Å2
ΔGint-23 kcal/mol
Surface area23810 Å2
MethodPISA
4
D: Tyrosine-protein kinase JAK2
P: Erythropoietin receptor


Theoretical massNumber of molelcules
Total (without water)64,7442
Polymers64,7442
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2760 Å2
ΔGint-23 kcal/mol
Surface area22830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)178.490, 114.880, 179.820
Angle α, β, γ (deg.)90.00, 93.21, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
Tyrosine-protein kinase JAK2 / Janus kinase 2 / JAK-2


Mass: 55805.508 Da / Num. of mol.: 4 / Fragment: FERM/SH2 (UNP residues 36-514)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Protein
Erythropoietin receptor / / EPOR / EPO-R


Mass: 8938.755 Da / Num. of mol.: 4 / Fragment: UNP residues 273-338
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EPOR / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P19235
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 145 / 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: 3.55 Å3/Da / Density % sol: 65.39 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 7.6 / Details: 100 mM Tris, pH 7.6, 2-4% PEG8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 3, 2017
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 2.65→48.44 Å / Num. obs: 104923 / % possible obs: 99.55 % / Redundancy: 3.4 % / Biso Wilson estimate: 60.45 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.07325 / Rpim(I) all: 0.04633 / Rrim(I) all: 0.08687 / Net I/σ(I): 13.1
Reflection shellResolution: 2.65→2.745 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.8652 / Mean I/σ(I) obs: 1.25 / Num. unique obs: 10236 / CC1/2: 0.631 / Rpim(I) all: 0.5555 / Rrim(I) all: 1.031 / % possible all: 97.9

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4Z32

4z32


Resolution: 2.65→48.44 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.32 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2625 1995 1.9 %
Rwork0.2253 --
obs0.226 104861 99.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.65→48.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms16454 0 0 145 16599
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00116884
X-RAY DIFFRACTIONf_angle_d0.37722879
X-RAY DIFFRACTIONf_dihedral_angle_d11.7510032
X-RAY DIFFRACTIONf_chiral_restr0.0392470
X-RAY DIFFRACTIONf_plane_restr0.0032915
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6504-2.71660.42811430.37247131X-RAY DIFFRACTION97
2.7166-2.79010.37031400.33437349X-RAY DIFFRACTION100
2.7901-2.87220.29231420.287334X-RAY DIFFRACTION100
2.8722-2.96490.30431460.27137313X-RAY DIFFRACTION100
2.9649-3.07080.3461410.27457305X-RAY DIFFRACTION100
3.0708-3.19370.34921420.28597412X-RAY DIFFRACTION100
3.1937-3.33910.30081430.28397312X-RAY DIFFRACTION100
3.3391-3.51510.28791460.25547339X-RAY DIFFRACTION100
3.5151-3.73520.29671370.22947364X-RAY DIFFRACTION100
3.7352-4.02350.23791440.20747333X-RAY DIFFRACTION100
4.0235-4.42810.21481460.18627418X-RAY DIFFRACTION100
4.4281-5.06830.20831430.17697354X-RAY DIFFRACTION100
5.0683-6.38320.23591460.21837412X-RAY DIFFRACTION100
6.3832-48.44780.23981360.19267490X-RAY DIFFRACTION99

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