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- PDB-3zmm: Inhibitors of Jak2 Kinase domain -

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Basic information

Entry
Database: PDB / ID: 3zmm
TitleInhibitors of Jak2 Kinase domain
ComponentsTYROSINE-PROTEIN KINASE JAK2
KeywordsTRANSFERASE
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
ACETYL GROUP / Chem-F9J / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsRead, J. / Green, I. / Pollard, H. / Howard, T. / Mott, R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Discovery of Novel Jak2-Stat Pathway Inhibitors with Extended Residence Time on Target.
Authors: Guan, H. / Lamb, M.L. / Peng, B. / Huang, S. / Degrace, N. / Read, J. / Hussain, S. / Wu, J. / Rivard, C. / Alimzhanov, M. / Bebernitz, G. / Bell, K. / Ye, M. / Zinda, M. / Ioannidis, S.
History
DepositionFeb 11, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 17, 2013Provider: repository / Type: Initial release
Revision 1.1May 8, 2013Group: Database references / Source and taxonomy
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3Dec 20, 2023Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms / 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_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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

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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)71,1617
Polymers70,1922
Non-polymers9695
Water2,522140
1
A: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6024
Polymers35,0961
Non-polymers5073
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5583
Polymers35,0961
Non-polymers4622
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.506, 126.688, 135.593
Angle α, β, γ (deg.)90.00, 97.22, 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: 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(DE3) / Variant (production host): STAR
References: UniProt: O60674, non-specific protein-tyrosine kinase, EC: 2.7.1.112
#2: Chemical ChemComp-F9J / 5-FLUORO-4-[(1S)-1-(5-FLUOROPYRIMIDIN-2-YL)ETHOXY]-N-(5-METHYL-1H-PYRAZOL-3-YL)-6-MORPHOLINO-PYRIMIDIN-2-AMINE


Mass: 418.401 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H20F2N8O2
#3: Chemical ChemComp-ACE / ACETYL GROUP


Mass: 44.053 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H4O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 140 / 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: 2.7 Å3/Da / Density % sol: 54.47 % / Description: NONE
Crystal growpH: 7.4 / Details: pH 7.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Dec 21, 2007 / 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: 2.5→17.57 Å / Num. obs: 24425 / % possible obs: 95 % / Observed criterion σ(I): 2 / Redundancy: 6.6 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 6.48
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 5.85 % / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 2.35 / % possible all: 83.2

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
MOSFLMdata reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2XA4

2xa4


Resolution: 2.51→17.57 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.921 / SU B: 19.256 / SU ML: 0.218 / Cross valid method: THROUGHOUT / ESU R: 0.534 / ESU R Free: 0.289 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24593 1239 5.1 %RANDOM
Rwork0.19257 ---
obs0.19541 23024 95.55 %-
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: 62.225 Å2
Baniso -1Baniso -2Baniso -3
1-0.92 Å20 Å20.08 Å2
2--0.02 Å20 Å2
3----0.92 Å2
Refinement stepCycle: LAST / Resolution: 2.51→17.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4495 0 69 140 4704
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0194681
X-RAY DIFFRACTIONr_bond_other_d0.0010.023196
X-RAY DIFFRACTIONr_angle_refined_deg1.461.9966322
X-RAY DIFFRACTIONr_angle_other_deg0.88737758
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2915550
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.69323.982226
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.55115828
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.3781534
X-RAY DIFFRACTIONr_chiral_restr0.0770.2670
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215185
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02955
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
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
LS refinement shellResolution: 2.514→2.578 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.597 72 -
Rwork0.491 1365 -
obs--79.04 %
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)
10.61130.0202-0.00212.0251-0.66561.92280.08680.0820.0315-0.1913-0.3763-0.1482-0.04880.32390.28960.206-0.06070.04370.19880.04860.05975.756213.095321.7308
21.0584-0.177-0.1310.99560.22010.9829-0.11920.0076-0.0220.00230.04630.00080.1792-0.08060.07290.2593-0.10550.0210.17370.03410.020923.7022-12.584246.3797
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A844 - 1130
2X-RAY DIFFRACTION2B843 - 1131

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