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- PDB-4e4m: JAK2 kinase (JH1 domain) in complex with compound 30 -

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Basic information

Entry
Database: PDB / ID: 4e4m
TitleJAK2 kinase (JH1 domain) in complex with compound 30
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / o-phosphotyrosine / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / symbiont-induced defense-related programmed cell death / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway ...interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / symbiont-induced defense-related programmed cell death / regulation of postsynapse to nucleus signaling pathway / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / thrombopoietin-mediated signaling pathway / Signaling by Erythropoietin / collagen-activated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / type 1 angiotensin receptor binding / post-embryonic hemopoiesis / interleukin-12 receptor complex / erythropoietin-mediated signaling pathway / interleukin-23 receptor complex / interleukin-23-mediated signaling pathway / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / positive regulation of MHC class II biosynthetic process / positive regulation of NK T cell proliferation / acetylcholine receptor binding / positive regulation of platelet activation / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / positive regulation of platelet aggregation / Signaling by Leptin / Interleukin-12 signaling / positive regulation of epithelial cell apoptotic process / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / regulation of nitric oxide biosynthetic process / growth hormone receptor binding / positive regulation of cell-substrate adhesion / axon regeneration / response to hydroperoxide / extrinsic component of cytoplasmic side of plasma membrane / regulation of receptor signaling pathway via JAK-STAT / negative regulation of cardiac muscle cell apoptotic process / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / positive regulation of tyrosine phosphorylation of STAT protein / negative regulation of cell-cell adhesion / extrinsic component of plasma membrane / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / peptide hormone receptor binding / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / MAPK3 (ERK1) activation / response to amine / Prolactin receptor signaling / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / mesoderm development / positive regulation of natural killer cell proliferation / positive regulation of interleukin-17 production / response to tumor necrosis factor / signaling receptor activator activity / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / insulin receptor substrate binding / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / cellular response to dexamethasone stimulus / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Growth hormone receptor signaling / Erythropoietin activates RAS / phosphatidylinositol 3-kinase binding / Signaling by CSF3 (G-CSF) / positive regulation of vascular associated smooth muscle cell proliferation / extrinsic apoptotic signaling pathway / actin filament polymerization / positive regulation of T cell proliferation / negative regulation of cytokine production involved in inflammatory response / SH2 domain binding / post-translational protein modification / lipopolysaccharide-mediated signaling pathway / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / positive regulation of interleukin-1 beta production / endosome lumen / positive regulation of apoptotic signaling pathway / erythrocyte differentiation / tumor necrosis factor-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity
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 / : ...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 / SH2 domain / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-0NH / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsEigenbrot, C.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors.
Authors: Kulagowski, J.J. / Blair, W. / Bull, R.J. / Chang, C. / Deshmukh, G. / Dyke, H.J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Harrison, T.K. / Hewitt, P.R. / Liimatta, M. / Hurley, C.A. / ...Authors: Kulagowski, J.J. / Blair, W. / Bull, R.J. / Chang, C. / Deshmukh, G. / Dyke, H.J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Harrison, T.K. / Hewitt, P.R. / Liimatta, M. / Hurley, C.A. / Johnson, A. / Johnson, T. / Kenny, J.R. / Bir Kohli, P. / Maxey, R.J. / Mendonca, R. / Mortara, K. / Murray, J. / Narukulla, R. / Shia, S. / Steffek, M. / Ubhayakar, S. / Ultsch, M. / van Abbema, A. / Ward, S.I. / Waszkowycz, B. / Zak, M.
History
DepositionMar 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 30, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 11, 2012Group: Database references
Revision 1.2Sep 13, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.4Oct 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: Tyrosine-protein kinase JAK2
B: Tyrosine-protein kinase JAK2
D: Tyrosine-protein kinase JAK2
E: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,2798
Polymers141,9454
Non-polymers1,3344
Water8,089449
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8202
Polymers35,4861
Non-polymers3331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8202
Polymers35,4861
Non-polymers3331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
D: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8202
Polymers35,4861
Non-polymers3331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
E: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8202
Polymers35,4861
Non-polymers3331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)69.366, 76.308, 87.278
Angle α, β, γ (deg.)75.27, 66.62, 62.96
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: 35486.254 Da / Num. of mol.: 4 / Fragment: protein kinase domain JH1, UNP residues 833-1132
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-0NH / 1-[4-methyl-1-(methylsulfonyl)piperidin-4-yl]-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine


Mass: 333.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H19N5O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 449 / 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: 2.65 Å3/Da / Density % sol: 53.58 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 6
Details: ammonium acetate, sodium citrate, PEG 8000, pH 6, VAPOR DIFFUSION, SITTING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 21, 2010 / Details: Si(111)
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.25→50 Å / Num. all: 66346 / Num. obs: 66346 / % possible obs: 96.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -2 / Redundancy: 2 % / Biso Wilson estimate: 26 Å2 / Rsym value: 0.107 / Net I/σ(I): 7.1
Reflection shellResolution: 2.25→2.33 Å / Mean I/σ(I) obs: 1.7 / Rsym value: 0.459 / % possible all: 95.9

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2B7A

2b7a


Resolution: 2.25→50 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.916 / SU B: 12.744 / SU ML: 0.161 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): -2 / ESU R: 0.29 / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24959 691 1 %RANDOM
Rwork0.1919 ---
all0.193 66346 --
obs0.1925 65651 96.25 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.52 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0.65 Å2-0.59 Å2
2--0.87 Å21.07 Å2
3----0.34 Å2
Refinement stepCycle: LAST / Resolution: 2.25→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9876 0 92 449 10417
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.02210196
X-RAY DIFFRACTIONr_bond_other_d0.0060.027160
X-RAY DIFFRACTIONr_angle_refined_deg1.1931.98313764
X-RAY DIFFRACTIONr_angle_other_deg0.852317360
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.54751188
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.29524.015528
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.338151888
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2831580
X-RAY DIFFRACTIONr_chiral_restr0.0690.21420
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211208
X-RAY DIFFRACTIONr_gen_planes_other0.0010.022084
X-RAY DIFFRACTIONr_nbd_refined0.2080.22098
X-RAY DIFFRACTIONr_nbd_other0.1950.27435
X-RAY DIFFRACTIONr_nbtor_refined0.1790.24894
X-RAY DIFFRACTIONr_nbtor_other0.0830.25317
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.150.2517
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0060.21
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.340.295
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2880.2245
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1840.225
X-RAY DIFFRACTIONr_mcbond_it3.4882.56212
X-RAY DIFFRACTIONr_mcbond_other0.5412.52400
X-RAY DIFFRACTIONr_mcangle_it4.56859608
X-RAY DIFFRACTIONr_scbond_it3.6812.54639
X-RAY DIFFRACTIONr_scangle_it5.01754156
LS refinement shellResolution: 2.252→2.374 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.298 98 -
Rwork0.236 9357 -
obs--94.62 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.66230.3183-0.53030.7157-0.6271.4795-0.033-0.0301-0.0242-0.02380.02540.0760.1037-0.02280.0076-0.0095-0.00610.0019-0.03240.0005-0.0160.8107-28.4223-26.4806
20.76810.0760.17360.3043-0.08530.36620.00720.05080.02390.0072-0.0108-0.01820.05340.0110.0036-0.0185-0.00130.0063-0.0092-0.0018-0.024418.2123-12.541-40.2709
30.5534-0.35410.75351.3019-0.64081.9758-0.00640.04850.0425-0.0198-0.05870.1541-0.1512-0.00510.0651-0.02740.0155-0.028-0.01580.0115-0.01350.5969-46.9404-51.6644
40.8189-0.0074-0.09320.30730.06310.35610.0276-0.0343-0.0249-0.0176-0.0288-0.0219-0.0394-0.00930.0012-0.0177-0.0011-0.0052-0.01070.0054-0.029318.2324-63.8878-38.9659
50.70730.2523-0.35111.4313-0.84671.9146-0.0464-0.0934-0.0648-0.0263-0.00370.16880.11610.00710.0501-0.0338-0.00940.0319-0.02170.0093-0.01390.5368-58.902312.8091
60.77740.06830.05890.32590.06310.39050.02760.01030.04880.0065-0.0274-0.02270.0368-0.0099-0.0002-0.02150.00170.0008-0.00760.0128-0.030218.2254-41.89970.1518
70.3896-0.24750.49160.6836-0.62151.9199-0.01870.0235-0.00470.01580.02270.0706-0.11430.0051-0.0039-0.02650.0054-0.0122-0.02560.0058-0.0078-33.8593-9.396-12.3464
80.6651-0.0791-0.21130.3304-0.040.4321-0.0018-0.0544-0.00790.0022-0.0129-0.013-0.06060.01870.0147-0.0141-0.0013-0.0111-0.0133-0.0008-0.0261-16.493-25.28211.4416
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A835 - 931
2X-RAY DIFFRACTION2A932 - 1132
3X-RAY DIFFRACTION3B835 - 931
4X-RAY DIFFRACTION4B932 - 1132
5X-RAY DIFFRACTION5D835 - 931
6X-RAY DIFFRACTION6D932 - 1132
7X-RAY DIFFRACTION7E835 - 931
8X-RAY DIFFRACTION8E932 - 1132

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