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- PDB-7t0p: JAK2 JH2 IN COMPLEX WITH JAK315 -

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Basic information

Entry
Database: PDB / ID: 7t0p
TitleJAK2 JH2 IN COMPLEX WITH JAK315
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/INHIBITOR / PSEUDOKINASE DOMAIN / INHIBITOR / COMPLEX / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX / SIGNALING PROTEIN / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


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 / Signaling by Erythropoietin ...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 / Signaling by Erythropoietin / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / 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 / interleukin-12 receptor complex / activation of Janus kinase activity / interleukin-23 receptor complex / positive regulation of platelet aggregation / tyrosine phosphorylation of STAT protein / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of T-helper 17 type immune response / positive regulation of platelet activation / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / acetylcholine receptor binding / cellular response to interleukin-3 / Signaling by Leptin / Interleukin-12 signaling / positive regulation of signaling receptor activity / 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 natural killer cell proliferation / positive regulation of epithelial cell apoptotic process / axon regeneration / growth hormone receptor signaling pathway / peptide hormone receptor binding / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / IFNG signaling activates MAPKs / Interleukin-20 family signaling / interleukin-6-mediated signaling pathway / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / positive regulation of interleukin-17 production / MAPK3 (ERK1) activation / negative regulation of DNA binding / response to amine / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / mesoderm development / positive regulation of SMAD protein signal transduction / cell surface receptor signaling pathway via JAK-STAT / platelet-derived growth factor receptor signaling pathway / 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 / extrinsic apoptotic signaling pathway / positive regulation of T cell proliferation / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / SH2 domain binding / post-translational protein modification / cellular response to dexamethasone stimulus / erythrocyte differentiation / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production / positive regulation of apoptotic signaling pathway / caveola / endosome lumen / positive regulation of cell differentiation
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 / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / 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
Chem-E3W / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsIppolito, J.A. / Liosi, M.-E. / Krimmer, S.G. / Schlessinger, J. / Jorgensen, W.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM32136 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: Insights on JAK2 Modulation by Potent, Selective, and Cell-Permeable Pseudokinase-Domain Ligands.
Authors: Liosi, M.E. / Ippolito, J.A. / Henry, S.P. / Krimmer, S.G. / Newton, A.S. / Cutrona, K.J. / Olivarez, R.A. / Mohanty, J. / Schlessinger, J. / Jorgensen, W.L.
History
DepositionNov 30, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 15, 2022Provider: repository / Type: Initial release
Revision 1.1Jul 6, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,6256
Polymers66,2422
Non-polymers1,3834
Water5,603311
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8133
Polymers33,1211
Non-polymers6922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,8133
Polymers33,1211
Non-polymers6922
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.430, 57.620, 59.670
Angle α, β, γ (deg.)88.240, 111.680, 92.480
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 33120.961 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-E3W / 4'-{[5-amino-3-(4-sulfamoylanilino)-1H-1,2,4-triazole-1-carbonyl]amino}-4-(benzyloxy)[1,1'-biphenyl]-3-carboxylic acid


Mass: 599.617 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H25N7O6S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 311 / 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: 2.29 Å3/Da / Density % sol: 46.18 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop
Details: 0.1M TRIS, PH 8.0 0.2M SODIUM ACETATE, 0.001 M TCEP, 12-24% PEG 4,000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU SATURN 944+ / Detector: CCD / Date: May 13, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.04→19.19 Å / Num. obs: 34789 / % possible obs: 93 % / Redundancy: 3.836 % / Biso Wilson estimate: 23.991 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.08 / Rrim(I) all: 0.094 / Χ2: 0.886 / Net I/σ(I): 13.38 / Num. measured all: 133449 / Scaling rejects: 833
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.04-2.183.680.2785.3121168675057520.9410.32685.2
2.18-2.353.8750.2047.4722269616557470.9740.23793.2
2.35-2.543.8850.1588.8618706511848150.9830.18494.1
2.54-2.783.9010.11810.5916919457843370.9910.13794.7
2.78-3.13.8980.08912.8715269410539170.9940.10395.4
3.1-3.573.880.05718.6713764369435470.9970.06696
3.57-4.353.8480.04126.7111580313730090.9980.04795.9
4.35-6.053.7860.03828.298851242723380.9980.04596.3
6.05-19.193.710.03730.514923143313270.9970.04492.6

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHENIX1.17.1_3660refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6occ

6occ


Resolution: 2.04→19.19 Å / SU ML: 0.24 / Cross valid method: THROUGHOUT / σ(F): 1.99 / Phase error: 27.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2474 1752 5.04 %
Rwork0.1945 33025 -
obs0.1973 34777 93.26 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 71.09 Å2 / Biso mean: 21.2521 Å2 / Biso min: 7.39 Å2
Refinement stepCycle: final / Resolution: 2.04→19.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4254 0 98 311 4663
Biso mean--19.28 24.88 -
Num. residues----546
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.04-2.10.33651060.25812058216476
2.1-2.160.27781310.22862521265292
2.16-2.230.29481280.20882546267493
2.23-2.310.27091400.22232497263793
2.31-2.40.28231240.20062601272594
2.4-2.510.28821390.20752548268794
2.51-2.640.28291400.2172595273595
2.64-2.80.26941380.20432594273295
2.8-3.020.25621440.20462580272495
3.02-3.320.23791370.19642617275496
3.32-3.80.23281400.17132624276496
3.8-4.770.2041360.16012634277096
4.77-19.190.20141490.18342610275996

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