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- PDB-2xa4: Inhibitors of Jak2 Kinase domain -

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Basic information

Entry
Database: PDB / ID: 2xa4
TitleInhibitors of Jak2 Kinase domain
ComponentsTYROSINE-PROTEIN KINASE JAK2
KeywordsTRANSFERASE / KINASE / MEMBRANE / ATP-BINDING / PROTO-ONCOGENE / PHOSPHOPROTEIN
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / : / 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 / : / 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-23-mediated signaling pathway / interleukin-12 receptor binding / Erythropoietin activates STAT5 / response to interleukin-12 / interleukin-5-mediated signaling pathway / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / interleukin-12 receptor complex / activation of Janus kinase activity / tyrosine phosphorylation of STAT protein / interleukin-23 receptor complex / Interleukin-23 signaling / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / positive regulation of MHC class II biosynthetic process / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / positive regulation of platelet activation / interleukin-3-mediated signaling pathway / cellular response to interleukin-3 / regulation of nitric oxide biosynthetic process / Signaling by Leptin / Interleukin-12 signaling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / positive regulation of signaling receptor activity / positive regulation of epithelial cell apoptotic process / 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 / growth hormone receptor signaling pathway / axon regeneration / response to hydroperoxide / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / extrinsic component of plasma membrane / peptide hormone receptor binding / Interleukin-20 family signaling / IFNG signaling activates MAPKs / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / MAPK3 (ERK1) activation / response to amine / negative regulation of DNA binding / extrinsic component of cytoplasmic side of plasma membrane / mesoderm development / positive regulation of nitric-oxide synthase biosynthetic process / positive regulation of interleukin-17 production / MAPK1 (ERK2) activation / 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 / type II interferon-mediated signaling pathway / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / response to tumor necrosis factor / phosphatidylinositol 3-kinase binding / Regulation of IFNG signaling / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / Growth hormone receptor signaling / positive regulation of T cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / post-translational protein modification / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / erythrocyte differentiation / positive regulation of interleukin-1 beta production / 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 / SH2 domain / 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 / SH2 domain / 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 / 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
Chem-AZ5 / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsRead, J. / Green, I. / Pollard, H. / Howard, T. / Mott, R.
CitationJournal: 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
DepositionMar 26, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 15, 2010Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2011Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Version format compliance
Revision 1.2Apr 1, 2015Group: Database references
Revision 1.3Mar 7, 2018Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_scientific_name ..._entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_scientific_name / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _entity_src_gen.pdbx_host_org_variant
Revision 1.4May 8, 2019Group: Data collection / Derived calculations / Experimental preparation
Category: exptl_crystal_grow / pdbx_seq_map_depositor_info / struct_conn
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp ..._exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_seq_map_depositor_info.one_letter_code_mod / _struct_conn.pdbx_leaving_atom_flag

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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)70,8614
Polymers70,1642
Non-polymers6982
Water5,549308
1
A: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4312
Polymers35,0821
Non-polymers3491
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4312
Polymers35,0821
Non-polymers3491
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.854, 126.741, 134.342
Angle α, β, γ (deg.)90.00, 97.04, 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: 35081.789 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) / Plasmid: PT7 3.3 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): star
References: UniProt: O60674, EC: 2.7.1.112, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-AZ5 / 5-CHLORO-N2-[(1S)-1-(5-FLUOROPYRIMIDIN-2-YL)ETHYL]-N4-(5-METHYL-1H-PYRAZOL-3-YL)PYRIMIDINE-2,4-DIAMINE


Mass: 348.766 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H14ClFN8
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, LYS 943 TO ALA ENGINEERED RESIDUE IN CHAIN A, LYS 945 TO ALA ...ENGINEERED RESIDUE IN CHAIN A, LYS 943 TO ALA ENGINEERED RESIDUE IN CHAIN A, LYS 945 TO ALA ENGINEERED RESIDUE IN CHAIN B, LYS 943 TO ALA ENGINEERED RESIDUE IN CHAIN B, LYS 945 TO ALA
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: 2.77 Å3/Da / Density % sol: 55.66 % / Description: NONE
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: HANGING DROP 20 DEG C. 1.5UL PROTEIN PLUS 1UL WELL PROTEIN: 8.7MG/ML IN 20MM TRIS/HCL PH 8.5, 100MM NACL, 1MM DTT WELL: 28% W/V PEG3350, 200MM AMMONIUM ACETATE, 100MM SODIUM CITRATE PH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873
DetectorType: ADSC CCD / Detector: CCD / Date: Mar 7, 2007 / Details: MIRRORS
RadiationMonochromator: SI111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 1.8→33.33 Å / Num. obs: 43209 / % possible obs: 93.4 % / Observed criterion σ(I): 2 / Redundancy: 3.04 % / Biso Wilson estimate: 22.815 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 8.02
Reflection shellResolution: 2.04→2.09 Å / Redundancy: 2.92 % / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 1.86 / % possible all: 87.2

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Processing

Software
NameVersionClassification
REFMAC5.5.0102refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.04→33.33 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.916 / SU B: 10.588 / SU ML: 0.131 / Cross valid method: THROUGHOUT / ESU R: 0.199 / ESU R Free: 0.179 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.U VALUES RESIDUAL ONLY. ATOM RECORD CONTAINS RESIDUAL B FACTORS ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.24456 2192 5.1 %RANDOM
Rwork0.19719 ---
obs0.19962 41003 93.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 26.225 Å2
Baniso -1Baniso -2Baniso -3
1-2.34 Å20 Å21.16 Å2
2--0.02 Å20 Å2
3----2.07 Å2
Refinement stepCycle: LAST / Resolution: 2.04→33.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4511 0 48 308 4867
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224658
X-RAY DIFFRACTIONr_bond_other_d0.0010.023201
X-RAY DIFFRACTIONr_angle_refined_deg1.3421.9836288
X-RAY DIFFRACTIONr_angle_other_deg0.85637772
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9275547
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.00924.053227
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.01915833
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.891532
X-RAY DIFFRACTIONr_chiral_restr0.0730.2670
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215147
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02951
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_it0.71.52761
X-RAY DIFFRACTIONr_mcbond_other0.1221.51116
X-RAY DIFFRACTIONr_mcangle_it1.32224446
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.76731897
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.9264.51842
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
LS refinement shellResolution: 2.04→2.093 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.29 161 -
Rwork0.269 2842 -
obs--87.14 %
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)
10.71830.1309-0.08622.2606-0.13331.14830.04530.04290.0078-0.2474-0.1848-0.1732-0.05110.10840.13950.03510.020.01410.03540.03240.03246.010612.864721.4735
21.05770.1446-0.25060.94020.37541.0481-0.0961-0.033-0.0511-0.0215-0.01530.07440.1112-0.07630.11130.0277-0.0161-0.00570.060.01670.048523.6035-12.397846.1857
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A843 - 1130
2X-RAY DIFFRACTION2B843 - 1131

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