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- PDB-4aqc: Triazolopyridine-based Inhibitor of Janus Kinase 2 -

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Basic information

Entry
Database: PDB / ID: 4aqc
TitleTriazolopyridine-based Inhibitor of Janus Kinase 2
ComponentsTYROSINE-PROTEIN KINASE JAK2
KeywordsTRANSFERASE / ATP-BINDING
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid 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 / nuclear receptor-mediated mineralocorticoid 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 / interleukin-12 receptor binding / Signaling by Erythropoietin / collagen-activated signaling pathway / Erythropoietin activates STAT5 / interleukin-5-mediated signaling pathway / response to interleukin-12 / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / post-embryonic hemopoiesis / interleukin-12 receptor complex / activation of Janus kinase activity / interleukin-23 receptor complex / tyrosine phosphorylation of STAT protein / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of platelet aggregation / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of platelet activation / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / acetylcholine receptor binding / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / Signaling by Leptin / regulation of nitric oxide biosynthetic process / 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 epithelial cell apoptotic process / positive regulation of natural killer cell proliferation / response to hydroperoxide / positive regulation of cell-substrate adhesion / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / axon regeneration / growth hormone receptor signaling pathway / peptide hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / intrinsic apoptotic signaling pathway in response to oxidative stress / IFNG signaling activates MAPKs / extrinsic component of plasma membrane / Interleukin-20 family signaling / interleukin-6-mediated signaling pathway / negative regulation of cell-cell adhesion / Interleukin-6 signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / enzyme-linked receptor protein signaling pathway / Prolactin receptor signaling / MAPK3 (ERK1) activation / positive regulation of interleukin-17 production / response to amine / negative regulation of DNA binding / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / cell surface receptor signaling pathway via JAK-STAT / mesoderm development / positive regulation of SMAD protein signal transduction / 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 / Regulation of IFNG signaling / type II interferon-mediated signaling pathway / Erythropoietin activates RAS / Growth hormone receptor signaling / positive regulation of T cell proliferation / extrinsic apoptotic signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic component of cytoplasmic side of plasma membrane / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / SH2 domain binding / cellular response to dexamethasone stimulus / erythrocyte differentiation / post-translational protein modification / 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 / positive regulation of apoptotic signaling pathway
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
Chem-88A / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsDugan, B.J. / Gingrich, D.E. / Mesaros, E.F. / Milkiewicz, K.L. / Curry, M.A. / Zulli, A.L. / Dobrzanski, P. / Serdikoff, C. / Jan, M. / Angeles, T.S. ...Dugan, B.J. / Gingrich, D.E. / Mesaros, E.F. / Milkiewicz, K.L. / Curry, M.A. / Zulli, A.L. / Dobrzanski, P. / Serdikoff, C. / Jan, M. / Angeles, T.S. / Albom, M.S. / Mason, J.L. / Aimone, L.D. / Meyer, S.L. / Huang, Z. / Wells-Knecht, K.J. / Ator, M.A. / Ruggeri, B.A. / Dorsey, B.D.
CitationJournal: J.Med.Chem. / Year: 2012
Title: A Selective, Orally Bioavailable 1,2,4-Triazolo[1,5-A]Pyridine-Based Inhibitor of Janus Kinase 2 for Use in Anticancer Therapy: Discovery of Cep-33779.
Authors: Dugan, B.J. / Gingrich, D.E. / Mesaros, E.F. / Milkiewicz, K.L. / Curry, M.A. / Zulli, A.L. / Dobrzanski, P. / Serdikoff, C. / Jan, M. / Angeles, T.S. / Albom, M.S. / Mason, J.L. / Aimone, L. ...Authors: Dugan, B.J. / Gingrich, D.E. / Mesaros, E.F. / Milkiewicz, K.L. / Curry, M.A. / Zulli, A.L. / Dobrzanski, P. / Serdikoff, C. / Jan, M. / Angeles, T.S. / Albom, M.S. / Mason, J.L. / Aimone, L.D. / Meyer, S.L. / Huang, Z. / Wells-Knecht, K.J. / Ator, M.A. / Ruggeri, B.A. / Dorsey, B.D.
History
DepositionApr 16, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 25, 2012Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2012Group: Other
Revision 1.2May 8, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_conn
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval / _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)72,2949
Polymers70,9152
Non-polymers1,3797
Water7,963442
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A: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0033
Polymers35,4571
Non-polymers5462
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TYROSINE-PROTEIN KINASE JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2916
Polymers35,4571
Non-polymers8345
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)111.679, 111.679, 70.422
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number76
Space group name H-MP41

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Components

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


Mass: 35457.320 Da / Num. of mol.: 2 / Fragment: KINASE DOMAIN, RESIDUES 835-1132
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-88A / 8-(4-methylsulfonylphenyl)-N-(4-morpholin-4-ylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine / [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-morpholin-4-yl-phenyl)-amine


Mass: 449.525 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H23N5O3S
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 442 / 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: 3.1 Å3/Da / Density % sol: 60.28 % / Description: NONE
Crystal growMethod: vapor diffusion, hanging drop
Details: 32% PEG 3350, 0.2 M AMMONIUM SULFATE, 0.1 M BIS-TRIS, PH 6.8, HANGING DROP VAPOUR DIFFUSION

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.976
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.9→29.79 Å / Num. obs: 67871 / % possible obs: 99.4 % / Observed criterion σ(I): 1.5 / Redundancy: 4 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 12.8
Reflection shellResolution: 1.9→2 Å / Redundancy: 4 % / Rmerge(I) obs: 0.79 / Mean I/σ(I) obs: 1.7 / % possible all: 99.9

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Processing

Software
NameVersionClassification
REFMAC5.5.0090Drefinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→29.79 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.946 / SU B: 7.855 / SU ML: 0.101 / Cross valid method: THROUGHOUT / ESU R: 0.124 / ESU R Free: 0.123 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.21656 3420 5 %RANDOM
Rwork0.17625 ---
obs0.17833 64398 99.18 %-
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: 41.774 Å2
Baniso -1Baniso -2Baniso -3
1-1.42 Å20 Å20 Å2
2--1.42 Å20 Å2
3----2.85 Å2
Refinement stepCycle: LAST / Resolution: 1.9→29.79 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4876 0 89 442 5407
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0225208
X-RAY DIFFRACTIONr_bond_other_d0.0020.023715
X-RAY DIFFRACTIONr_angle_refined_deg1.4521.9917046
X-RAY DIFFRACTIONr_angle_other_deg0.90238993
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8525618
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.05523.556270
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.05215975
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1871548
X-RAY DIFFRACTIONr_chiral_restr0.0890.2721
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215723
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021111
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_it2.06722986
X-RAY DIFFRACTIONr_mcbond_other0.58421206
X-RAY DIFFRACTIONr_mcangle_it3.24834853
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.41222222
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.76832179
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: 1.9→1.949 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.339 254 -
Rwork0.331 4732 -
obs--99.42 %
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)
11.4868-0.14271.03381.7299-0.31884.25330.21510.0855-0.2599-0.00610.007-0.09360.50550.3655-0.22210.08070.0411-0.01480.0332-0.02210.1921122.73960.3257.163
22.4897-0.9677-1.19732.73010.77131.73090.0851-0.07740.11220.0551-0.00290.0387-0.25590.0781-0.08210.0627-0.0070.02880.0888-0.01610.109684.126118.42423.7
31.5191-0.35750.36491.11810.30623.2765-0.0355-0.0527-0.0977-0.00520.03190.0707-0.1661-0.38940.00350.04290.02850.03420.05270.01280.1112102.99472.867-2.902
41.4074-0.41940.98091.5628-0.5752.20630.0244-0.1534-0.0771-0.0470.044-0.0290.16950.0072-0.06840.04050.05240.00870.1266-0.02380.11783.88693.97216.492
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A843 - 935
2X-RAY DIFFRACTION2B843 - 935
3X-RAY DIFFRACTION3A936 - 1131
4X-RAY DIFFRACTION4B936 - 1131

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