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- PDB-4c62: Inhibitors of Jak2 Kinase domain -

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Basic information

Entry
Database: PDB / ID: 4c62
TitleInhibitors of Jak2 Kinase domain
ComponentsTYROSINE-PROTEIN KINASE JAK2
KeywordsTRANSFERASE
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 / granulocyte macrophage colony-stimulating factor receptor complex ...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 / 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 / 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 / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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
ACETATE ION / Chem-XWW / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsRead, J. / Green, I. / Pollard, H. / Howard, T.
Citation
Journal: J.Med.Chem. / Year: 2014
Title: Discovery of 1-Methyl-1H-Imidazole Derivatives as Potent Jak2 Inhibitors.
Authors: Su, Q. / Ioannidis, S. / Chuaqui, C. / Almeida, L. / Alimzhanov, M. / Bebernitz, G. / Bell, K. / Block, M. / Howard, T. / Huang, S. / Huszar, D. / Read, J.A. / Rivard Costa, C. / Shi, J. / ...Authors: Su, Q. / Ioannidis, S. / Chuaqui, C. / Almeida, L. / Alimzhanov, M. / Bebernitz, G. / Bell, K. / Block, M. / Howard, T. / Huang, S. / Huszar, D. / Read, J.A. / Rivard Costa, C. / Shi, J. / Su, M. / Ye, M. / Zinda, M.
#1: Journal: J.Med.Chem. / Year: 2011
Title: Discovery of 5-Chloro-N2-[(1S)-1-(5-Fluoropyrimidin-2-Yl)Ethyl]-N4-(5-Methyl-1H-Pyrazol-3-Yl)Pyrimidine-2,4-Diamine (Azd1480) as a Novel Inhibitor of the Jak/Stat Pathway.
Authors: Ioannidis, S. / Lamb, M.L. / Wang, T. / Almeida, L. / Block, M.H. / Davies, A.M. / Peng, B. / Su, M. / Zhang, H. / Hoffmann, E. / Rivard, C. / Green, I. / Howard, T. / Pollard, H. / Read, J. ...Authors: Ioannidis, S. / Lamb, M.L. / Wang, T. / Almeida, L. / Block, M.H. / Davies, A.M. / Peng, B. / Su, M. / Zhang, H. / Hoffmann, E. / Rivard, C. / Green, I. / Howard, T. / Pollard, H. / Read, J. / Alimzhanov, M. / Bebernitz, G. / Bell, K. / Ye, M. / Huszar, D. / Zinda, M.
History
DepositionSep 17, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 8, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2014Group: Database references
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,1707
Polymers70,1922
Non-polymers9785
Water2,108117
1
A: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6144
Polymers35,0961
Non-polymers5193
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5553
Polymers35,0961
Non-polymers4592
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.507, 126.889, 135.875
Angle α, β, γ (deg.)90.00, 97.53, 90.00
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain: (Details: A)
NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.78088, -0.624678, -0.00173), (-0.624666, 0.780878, -0.004741), (0.004312, -0.002621, -0.999987)-8.19052, 17.27127, 66.70859

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Components

#1: Protein TYROSINE-PROTEIN KINASE JAK2 / JANUS KINASE 2 / JAK-2


Mass: 35095.816 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN RESIDUES 835-1132 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): STAR
References: UniProt: O60674, EC: 2.7.1.112, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-XWW / N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-n4-(1-methylimidazol-4-yl)-6-morpholino-1,3,5-triazine-2,4-diamine


Mass: 400.413 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H21FN10O
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 117 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsK943 AND K945A DOUBLE MUTANT

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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: 2.82 Å3/Da / Density % sol: 56.4 % / Description: NONE
Crystal growpH: 7 / Details: pH 7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Jun 18, 2008 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.75→21.2 Å / Num. obs: 19353 / % possible obs: 99.4 % / Observed criterion σ(I): 2 / Redundancy: 4 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 11.6
Reflection shellResolution: 2.75→2.9 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 2.1 / % possible all: 98.7

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
MOSFLMdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2XA4

2xa4


Resolution: 2.75→21 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.903 / SU B: 25.38 / SU ML: 0.259 / Cross valid method: THROUGHOUT / ESU R Free: 0.345 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.24568 991 5.1 %RANDOM
Rwork0.19649 ---
obs0.19906 18362 99.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 50.193 Å2
Baniso -1Baniso -2Baniso -3
1-2.57 Å20 Å20.5 Å2
2--0.31 Å20 Å2
3----2.84 Å2
Refinement stepCycle: LAST / Resolution: 2.75→21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4420 0 67 117 4604
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0194581
X-RAY DIFFRACTIONr_bond_other_d0.0050.024249
X-RAY DIFFRACTIONr_angle_refined_deg1.6991.9946192
X-RAY DIFFRACTIONr_angle_other_deg1.52539740
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8835540
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.7124.074216
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.06415785
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.9181531
X-RAY DIFFRACTIONr_chiral_restr0.070.2665
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0215175
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021048
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.2623.8012187
X-RAY DIFFRACTIONr_mcbond_other2.263.7982183
X-RAY DIFFRACTIONr_mcangle_it3.885.6772716
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.3023.9782394
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCSNumber: 2444 / Type: tight thermal / Rms dev position: 7.06 Å / Weight position: 0.5
LS refinement shellResolution: 2.75→2.82 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.348 64 -
Rwork0.292 1335 -
obs--98.18 %
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)
10.0947-0.3513-0.12912.09310.52311.71790.04870.0741-0.01950.0482-0.36840.1239-0.079-0.29320.31970.060.01310.00010.1119-0.06280.07157.817413.190345.6045
20.5788-0.1698-0.3140.3457-0.21850.9173-0.1917-0.08510.08690.01030.0733-0.04490.19110.08590.11840.11220.0812-0.02080.1203-0.00970.0864-10.2666-12.50121.1052
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A844 - 1130
2X-RAY DIFFRACTION2B843 - 1131

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