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- PDB-7q7l: JAK2 in complex with 4-(2-amino-8-{[(2S)-1-hydroxypropan-2-yl]ami... -

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Basic information

Entry
Database: PDB / ID: 7q7l
TitleJAK2 in complex with 4-(2-amino-8-{[(2S)-1-hydroxypropan-2-yl]amino}quinazolin-6-yl)-5-ethyl-2-fluorophenol
ComponentsTyrosine-protein kinase JAK2
KeywordsSIGNALING PROTEIN / JAK2 / Janus kinase 2
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 / interleukin-12 receptor complex / activation of Janus kinase activity / 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 T-helper 17 type immune response / positive regulation of platelet activation / 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 / Interleukin-12 signaling / positive regulation of signaling receptor activity / 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 / growth hormone receptor signaling pathway / peptide hormone receptor binding / intrinsic apoptotic signaling pathway in response to oxidative stress / IFNG signaling activates MAPKs / extrinsic component of plasma membrane / positive regulation of natural killer cell proliferation / Interleukin-20 family signaling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / negative regulation of cell-cell adhesion / Interleukin-6 signaling / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / 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 SMAD protein signal transduction / mesoderm development / 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 / extrinsic apoptotic signaling pathway / positive regulation of T cell proliferation / Signaling by CSF3 (G-CSF) / positive regulation of apoptotic signaling pathway / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / tumor necrosis factor-mediated signaling pathway / extrinsic component of cytoplasmic side of plasma membrane / actin filament polymerization / SH2 domain binding / post-translational protein modification / cellular response to dexamethasone stimulus / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-9I2 / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.97 Å
AuthorsRowland, P.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Investigation of Janus Kinase (JAK) Inhibitors for Lung Delivery and the Importance of Aldehyde Oxidase Metabolism.
Authors: Wellaway, C.R. / Baldwin, I.R. / Bamborough, P. / Barker, D. / Bartholomew, M.A. / Chung, C.W. / Dumpelfeld, B. / Evans, J.P. / Fazakerley, N.J. / Homes, P. / Keeling, S.P. / Lewell, X.Q. / ...Authors: Wellaway, C.R. / Baldwin, I.R. / Bamborough, P. / Barker, D. / Bartholomew, M.A. / Chung, C.W. / Dumpelfeld, B. / Evans, J.P. / Fazakerley, N.J. / Homes, P. / Keeling, S.P. / Lewell, X.Q. / McNab, F.W. / Morley, J. / Needham, D. / Neu, M. / van Oosterhout, A.J.M. / Pal, A. / Reinhard, F.B.M. / Rianjongdee, F. / Robertson, C.M. / Rowland, P. / Shah, R.R. / Sherriff, E.B. / Sloan, L.A. / Teague, S. / Thomas, D.A. / Wellaway, N. / Wojno-Picon, J. / Woolven, J.M. / Coe, D.M.
History
DepositionNov 9, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 2, 2022Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9033
Polymers37,4541
Non-polymers4482
Water3,513195
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area270 Å2
ΔGint0 kcal/mol
Surface area14040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.290, 100.980, 67.460
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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Components

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


Mass: 37454.301 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Baculovirus expression vector pFastBac1-HM
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-9I2 / 4-[2-azanyl-8-[[(2~{S})-1-oxidanylpropan-2-yl]amino]quinazolin-6-yl]-5-ethyl-2-fluoranyl-phenol


Mass: 356.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H21FN4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 195 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.12 Å3/Da / Density % sol: 42.01 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 1.46-1.60 M trisodium citrate (untitrated)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.97296 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 6, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97296 Å / Relative weight: 1
ReflectionResolution: 1.97→67 Å / Num. obs: 22924 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.999 / Rrim(I) all: 0.078 / Net I/σ(I): 16.7
Reflection shellResolution: 1.97→1.98 Å / Mean I/σ(I) obs: 2 / Num. unique obs: 213 / CC1/2: 0.849 / Rrim(I) all: 0.973

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: apo

Resolution: 1.97→50.49 Å / Cor.coef. Fo:Fc: 0.9547 / Cor.coef. Fo:Fc free: 0.948 / SU R Cruickshank DPI: 0.155 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.164 / SU Rfree Blow DPI: 0.133 / SU Rfree Cruickshank DPI: 0.13
RfactorNum. reflection% reflectionSelection details
Rfree0.1956 1138 4.97 %RANDOM
Rwork0.1705 ---
obs0.1718 22892 99.95 %-
Displacement parametersBiso max: 121.21 Å2 / Biso mean: 42.36 Å2 / Biso min: 21.35 Å2
Baniso -1Baniso -2Baniso -3
1-7.1238 Å20 Å20 Å2
2---6.7066 Å20 Å2
3----0.4173 Å2
Refine analyzeLuzzati coordinate error obs: 0.212 Å
Refinement stepCycle: final / Resolution: 1.97→50.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2393 0 32 195 2620
Biso mean--40.42 51.43 -
Num. residues----289
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d912SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes71HARMONIC2
X-RAY DIFFRACTIONt_gen_planes379HARMONIC5
X-RAY DIFFRACTIONt_it2497HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion302SEMIHARMONIC5
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_contact3050SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2497HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3370HARMONIC21.01
X-RAY DIFFRACTIONt_omega_torsion3.14
X-RAY DIFFRACTIONt_other_torsion17.62
LS refinement shellResolution: 1.97→2.07 Å / Rfactor Rfree error: 0 / Total num. of bins used: 11
RfactorNum. reflection% reflection
Rfree0.2076 123 4.11 %
Rwork0.1957 2867 -
all0.1962 2990 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 28.728 Å / Origin y: 19.8015 Å / Origin z: 70.6537 Å
111213212223313233
T-0.0742 Å2-0.0138 Å20.0037 Å2--0.0329 Å2-0.0307 Å2---0.078 Å2
L1.3891 °2-0.3854 °2-0.1399 °2-0.8035 °20.1216 °2--0.7078 °2
S-0.0593 Å °0.0311 Å °-0.0389 Å °0.0231 Å °0.0195 Å °0.027 Å °-0.0067 Å °-0.0551 Å °0.0398 Å °
Refinement TLS groupSelection details: { A|* }

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