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- PDB-6aaj: Crystal structure of JAK2 in complex with peficitinib -

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Basic information

Entry
Database: PDB / ID: 6aaj
TitleCrystal structure of JAK2 in complex with peficitinib
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/INHIBITOR / protein kinase / TRANSFERASE-INHIBITOR complex
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-9T6 / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.37 Å
AuthorsAmano, Y. / Tateishi, Y.
CitationJournal: Bioorg. Med. Chem. / Year: 2018
Title: Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor
Authors: Hamaguchi, H. / Amano, Y. / Moritomo, A. / Shirakami, S. / Nakajima, Y. / Nakai, K. / Nomura, N. / Ito, M. / Higashi, Y. / Inoue, T.
History
DepositionJul 18, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 15, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 12, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed
Revision 1.2Oct 24, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 8, 2023Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_assembly ...database_2 / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)70,9304
Polymers70,2782
Non-polymers6532
Water75742
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4652
Polymers35,1391
Non-polymers3261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4652
Polymers35,1391
Non-polymers3261
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.148, 126.657, 132.908
Angle α, β, γ (deg.)90.00, 96.49, 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: 35138.840 Da / Num. of mol.: 2 / Fragment: UNP residues 834-1132 / Mutation: K943A, K945A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Escherichia coli (E. coli)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-9T6 / 4-[[(1S,3R)-5-oxidanyl-2-adamantyl]amino]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide


Mass: 326.393 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H22N4O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 42 / 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: 2.74 Å3/Da / Density % sol: 55.16 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 50mM sodium citrate(pH6.5), 100mM ammonium phosphate, 20% PEG4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS VII / Detector: IMAGE PLATE / Date: Mar 24, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.37→45.7 Å / Num. obs: 28679 / % possible obs: 99.6 % / Redundancy: 3.8 % / Rmerge(I) obs: 0.043 / Net I/σ(I): 16.4
Reflection shellResolution: 2.37→2.46 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.494 / Mean I/σ(I) obs: 2.2 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
XDSdata reduction
XSCALEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.37→19.24 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.936 / SU B: 10.744 / SU ML: 0.241 / Cross valid method: THROUGHOUT / ESU R: 0.369 / ESU R Free: 0.261 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.26163 1386 4.8 %RANDOM
Rwork0.20819 ---
obs0.21074 27293 99.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 59.196 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å2-0 Å2-0.01 Å2
2---0.02 Å2-0 Å2
3---0.04 Å2
Refinement stepCycle: 1 / Resolution: 2.37→19.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4575 0 48 42 4665
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0154724
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3641.7726382
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2715549
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.63219.418189
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.33215726
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.1811533
X-RAY DIFFRACTIONr_chiral_restr0.0910.2582
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0213629
X-RAY DIFFRACTIONr_gen_planes_other
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_it3.5635.7322220
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it5.7098.5672761
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.1416.1032503
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined9.57677.296780
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: 2.37→2.431 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.349 125 -
Rwork0.324 1987 -
obs--99.76 %

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