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- PDB-5cf8: CRYSTAL STRUCTURE OF JANUS KINASE 2 IN COMPLEX WITH N,N-DICYCLOPR... -

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Basic information

Entry
Database: PDB / ID: 5cf8
TitleCRYSTAL STRUCTURE OF JANUS KINASE 2 IN COMPLEX WITH N,N-DICYCLOPROPYL-10-ETHYL-7-[(3-METHOXYPROPYL)AMINO] -3-METHYL-3,5,8,10-TETRAAZATRICYCLO[7.3.0.0,6] DODECA-1(9),2(6),4,7,11-PENTAENE-11-CARBOXAMIDE
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / KINASE / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


interleukin-35-mediated signaling pathway / 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 / granulocyte macrophage colony-stimulating factor receptor complex ...interleukin-35-mediated signaling pathway / 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 / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / Signaling by Erythropoietin / 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 / positive regulation of platelet activation / positive regulation of MHC class II biosynthetic process / Interleukin-23 signaling / positive regulation of T-helper 17 type immune response / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / regulation of nitric oxide biosynthetic process / acetylcholine receptor binding / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / 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 / response to hydroperoxide / positive regulation of cell-substrate adhesion / negative regulation of cardiac muscle cell apoptotic process / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / 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 / extrinsic component of plasma membrane / IFNG signaling activates MAPKs / 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 / mesoderm development / positive regulation of natural killer cell proliferation / 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 / extrinsic apoptotic signaling pathway / positive regulation of 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-50V / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.8 Å
AuthorsSack, J.S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2015
Title: Discovery of a Highly Selective JAK2 Inhibitor, BMS-911543, for the Treatment of Myeloproliferative Neoplasms.
Authors: Wan, H. / Schroeder, G.M. / Hart, A.C. / Inghrim, J. / Grebinski, J. / Tokarski, J.S. / Lorenzi, M.V. / You, D. / Mcdevitt, T. / Penhallow, B. / Vuppugalla, R. / Zhang, Y. / Gu, X. / Iyer, R. ...Authors: Wan, H. / Schroeder, G.M. / Hart, A.C. / Inghrim, J. / Grebinski, J. / Tokarski, J.S. / Lorenzi, M.V. / You, D. / Mcdevitt, T. / Penhallow, B. / Vuppugalla, R. / Zhang, Y. / Gu, X. / Iyer, R. / Lombardo, L.J. / Trainor, G.L. / Ruepp, S. / Lippy, J. / Blat, Y. / Sack, J.S. / Khan, J.A. / Stefanski, K. / Sleczka, B. / Mathur, A. / Sun, J.H. / Wong, M.K. / Wu, D.R. / Li, P. / Gupta, A. / Arunachalam, P.N. / Pragalathan, B. / Narayanan, S. / K C, N. / Kuppusamy, P. / Purandare, A.V.
History
DepositionJul 8, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2015Group: Database references
Revision 1.2Nov 22, 2017Group: Derived calculations / Refinement description / Category: pdbx_struct_oper_list / software
Item: _pdbx_struct_oper_list.symmetry_operation / _software.name

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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)72,2564
Polymers71,3912
Non-polymers8652
Water8,881493
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1282
Polymers35,6961
Non-polymers4331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1282
Polymers35,6961
Non-polymers4331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)112.160, 112.160, 70.670
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: 35695.613 Da / Num. of mol.: 2 / Fragment: CATALYTIC DOMAIN, UNP RESIDUES 839-1132
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-50V / N,N-dicyclopropyl-4-[(1,5-dimethyl-1H-pyrazol-3-yl)amino]-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide


Mass: 432.521 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H28N8O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 493 / 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 Å3/Da / Density % sol: 58.95 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100MM MES BUFFER, 100MM NACL, 28% (w/v) PEG3350, 2MM DTT, AND 200MM TRI-SODIUM CITRATE
PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.9793 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Feb 27, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
20.97931
ReflectionResolution: 1.8→50 Å / Num. obs: 80713 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 29.49 Å2 / Rmerge(I) obs: 0.055 / Net I/σ(I): 22.5
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.494 / Mean I/σ(I) obs: 2.7 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
HKL-2000(DENZO)data reduction
HKL-2000(SCALEPACK)data scaling
RefinementResolution: 1.8→26.06 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.9551 / SU R Cruickshank DPI: 0.102 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.106 / SU Rfree Blow DPI: 0.096 / SU Rfree Cruickshank DPI: 0.094
RfactorNum. reflection% reflectionSelection details
Rfree0.2038 1652 2.05 %RANDOM
Rwork0.1908 ---
obs0.1911 80634 99.17 %-
Displacement parametersBiso mean: 35.18 Å2
Baniso -1Baniso -2Baniso -3
1--2.0444 Å20 Å20 Å2
2---2.0444 Å20 Å2
3---4.0887 Å2
Refine analyzeLuzzati coordinate error obs: 0.236 Å
Refinement stepCycle: LAST / Resolution: 1.8→26.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4674 0 64 493 5231
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.014918HARMONIC2
X-RAY DIFFRACTIONt_angle_deg16653HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1756SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes134HARMONIC2
X-RAY DIFFRACTIONt_gen_planes760HARMONIC5
X-RAY DIFFRACTIONt_it4918HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.44
X-RAY DIFFRACTIONt_other_torsion17.33
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion595SEMIHARMONIC5
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_contact6035SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2765 116 2.12 %
Rwork0.2538 5362 -
all0.2543 5478 -
obs--91.13 %

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