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- PDB-5tq8: Design and Synthesis of a pan-JAK Kinase Inhibitor Clinical Candi... -

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Basic information

Entry
Database: PDB / ID: 5tq8
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 / intracellular mineralocorticoid receptor 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 / Signaling by Erythropoietin ...interleukin-35-mediated signaling pathway / intracellular mineralocorticoid receptor 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 / Signaling by Erythropoietin / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / interleukin-12 receptor binding / post-embryonic hemopoiesis / collagen-activated signaling pathway / Erythropoietin activates STAT5 / Erythropoietin activates Phospholipase C gamma (PLCG) / interleukin-5-mediated signaling pathway / response to interleukin-12 / positive regulation of leukocyte proliferation / activation of Janus kinase activity / interleukin-12 receptor complex / interleukin-23 receptor complex / positive regulation of platelet aggregation / tyrosine phosphorylation of STAT protein / Interleukin-23 signaling / positive regulation of MHC class II biosynthetic process / positive regulation of platelet activation / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / acetylcholine receptor binding / cellular response to interleukin-3 / Signaling by Leptin / 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 cell-substrate adhesion / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / negative regulation of cardiac muscle cell apoptotic process / positive regulation of epithelial cell apoptotic process / axon regeneration / peptide hormone receptor binding / growth hormone receptor signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / IFNG signaling activates MAPKs / extrinsic component of plasma membrane / Interleukin-20 family signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / negative regulation of cell-cell adhesion / Prolactin receptor signaling / positive regulation of interleukin-17 production / negative regulation of DNA binding / MAPK3 (ERK1) activation / response to amine / positive regulation of nitric-oxide synthase biosynthetic process / MAPK1 (ERK2) activation / positive regulation of natural killer cell proliferation / mesoderm development / 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 / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / phosphatidylinositol 3-kinase binding / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Erythropoietin activates RAS / Growth hormone receptor signaling / positive regulation of apoptotic signaling pathway / extrinsic apoptotic signaling pathway / Signaling by CSF3 (G-CSF) / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of T cell proliferation / tumor necrosis factor-mediated signaling pathway / actin filament polymerization / extrinsic component of cytoplasmic side of plasma membrane / SH2 domain binding / cellular response to dexamethasone stimulus / post-translational protein modification / erythrocyte differentiation / 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
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-7GS / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.59 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 1.3Sep 27, 2017Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 1.4Oct 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4402
Polymers34,8741
Non-polymers5671
Water4,216234
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.740, 44.980, 52.350
Angle α, β, γ (deg.)104.91, 109.59, 94.10
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 34873.730 Da / Num. of mol.: 1 / Fragment: UNP residues 837-1132 / Mutation: M1073S, F1076T
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-7GS / {2-[6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-2H-indazol-3-yl]-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl}[5-(piperidin-1-yl)pyrazin-2-yl]methanone


Mass: 566.629 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H31FN8O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 234 / 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: 2.22 Å3/Da / Density % sol: 44.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.5
Details: 0.1 M Hepes, pH 7.5, 100 mM sodium acetate, 30% PEG-3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 14, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.59→43 Å / Num. obs: 38072 / % possible obs: 95 % / Redundancy: 1.8 % / Biso Wilson estimate: 21.93 Å2 / Rmerge(I) obs: 0.08 / Net I/σ(I): 8.2

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Processing

Software
NameVersionClassification
BUSTER2.9.6refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3tjc

3tjc


Resolution: 1.59→22.69 Å / Cor.coef. Fo:Fc: 0.9564 / Cor.coef. Fo:Fc free: 0.952 / SU R Cruickshank DPI: 0.084 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.085 / SU Rfree Blow DPI: 0.083 / SU Rfree Cruickshank DPI: 0.083
RfactorNum. reflection% reflectionSelection details
Rfree0.1923 1911 5.02 %RANDOM
Rwork0.1655 ---
obs0.1668 38052 94.18 %-
Displacement parametersBiso mean: 30.44 Å2
Baniso -1Baniso -2Baniso -3
1--4.2661 Å20.8539 Å25.5178 Å2
2--1.6217 Å2-1.0565 Å2
3---2.6444 Å2
Refine analyzeLuzzati coordinate error obs: 0.194 Å
Refinement stepCycle: 1 / Resolution: 1.59→22.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2390 0 42 234 2666
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012490HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.023362HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d888SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes85HARMONIC2
X-RAY DIFFRACTIONt_gen_planes361HARMONIC5
X-RAY DIFFRACTIONt_it2490HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion17.51
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion303SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3026SEMIHARMONIC4
LS refinement shellResolution: 1.59→1.63 Å / Total num. of bins used: 19
RfactorNum. reflection% reflection
Rfree0.2199 154 5.54 %
Rwork0.2006 2625 -
all0.2016 2779 -
obs--94.18 %
Refinement TLS params.Method: refined / Origin x: 1.3256 Å / Origin y: 0.84 Å / Origin z: 0.3736 Å
111213212223313233
T-0.0443 Å2-0.0151 Å2-0.0108 Å2--0.0531 Å20.0149 Å2---0.0307 Å2
L0.5168 °2-0.0852 °20.7914 °2-0.3398 °20.0404 °2--2.3729 °2
S-0.0447 Å °0.043 Å °0.0281 Å °0.0392 Å °-0.0495 Å °-0.0257 Å °-0.1196 Å °0.1303 Å °0.0941 Å °
Refinement TLS groupSelection details: { A|* }

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