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- PDB-5tq7: Design and Synthesis of a pan-JAK Kinase Inhibitor Clinical Candi... -

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Entry
Database: PDB / ID: 5tq7
TitleDesign and Synthesis of a pan-JAK Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin
ComponentsTyrosine-protein kinase JAK2
KeywordsTransferase/Transferase Inhibitor / Kinase / Inflammation / Jak Inhibitor / Transferase-Transferase Inhibitor complex
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
Chem-7GT / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsChrencik, J. / Jones, P.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin.
Authors: Jones, P. / Storer, R.I. / Sabnis, Y.A. / Wakenhut, F.M. / Whitlock, G.A. / England, K.S. / Mukaiyama, T. / Dehnhardt, C.M. / Coe, J.W. / Kortum, S.W. / Chrencik, J.E. / Brown, D.G. / Jones, ...Authors: Jones, P. / Storer, R.I. / Sabnis, Y.A. / Wakenhut, F.M. / Whitlock, G.A. / England, K.S. / Mukaiyama, T. / Dehnhardt, C.M. / Coe, J.W. / Kortum, S.W. / Chrencik, J.E. / Brown, D.G. / Jones, R.M. / Murphy, J.R. / Yeoh, T. / Morgan, P. / Kilty, I.
History
DepositionOct 23, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 11, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2017Group: Database references
Revision 1.2Feb 8, 2017Group: Database references
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.4Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.5Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)72,7514
Polymers71,7852
Non-polymers9652
Water3,927218
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3752
Polymers35,8931
Non-polymers4831
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,3752
Polymers35,8931
Non-polymers4831
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.061, 185.108, 52.492
Angle α, β, γ (deg.)90.00, 110.64, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein kinase JAK2 / Janus kinase 2 / JAK-2


Mass: 35892.656 Da / Num. of mol.: 2 / Fragment: UNP residues 837-1132 / Mutation: M1073S, F1076T, I1126V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Homo sapiens (human)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-7GT / {(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}[(3R)-3-(phenylsulfonyl)pyrrolidin-1-yl]methanone


Mass: 482.598 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H30N6O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 218 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.35 Å3/Da / Density % sol: 47.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.5
Details: 0.1 M Hepes, pH 7.5, 100 mM sodium acetate, 30% PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 2, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→33.68 Å / Num. obs: 30766 / % possible obs: 71 % / Redundancy: 2 % / Rmerge(I) obs: 0.2 / Net I/σ(I): 13.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3tjc

3tjc


Resolution: 2.1→33.68 Å / Cor.coef. Fo:Fc: 0.912 / Cor.coef. Fo:Fc free: 0.866 / SU B: 6.753 / SU ML: 0.183 / Cross valid method: THROUGHOUT / ESU R: 0.397 / ESU R Free: 0.279 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.28575 1468 5.1 %RANDOM
Rwork0.2258 ---
obs0.22891 27533 75.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.78 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0 Å20.01 Å2
2--0 Å20 Å2
3----0 Å2
Refinement stepCycle: 1 / Resolution: 2.1→33.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4475 0 68 218 4761
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0194643
X-RAY DIFFRACTIONr_bond_other_d0.0040.024413
X-RAY DIFFRACTIONr_angle_refined_deg1.6931.9796267
X-RAY DIFFRACTIONr_angle_other_deg1.083310157
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3615537
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.5824.378217
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.00515833
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8821526
X-RAY DIFFRACTIONr_chiral_restr0.0940.2670
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025281
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021065
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_it2.4092.3962181
X-RAY DIFFRACTIONr_mcbond_other2.4092.3952180
X-RAY DIFFRACTIONr_mcangle_it3.3133.5662707
X-RAY DIFFRACTIONr_mcangle_other3.3133.5682708
X-RAY DIFFRACTIONr_scbond_it2.9812.7352462
X-RAY DIFFRACTIONr_scbond_other2.9812.7362463
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.3383.9923561
X-RAY DIFFRACTIONr_long_range_B_refined6.44522.51419248
X-RAY DIFFRACTIONr_long_range_B_other6.44522.51419249
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.1→2.154 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 100 -
Rwork0.238 1937 -
obs--73.22 %

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