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- PDB-6bbv: Crystal Structure of JAK2 in complex with compound 25 -

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Basic information

Entry
Database: PDB / ID: 6bbv
TitleCrystal Structure of JAK2 in complex with compound 25
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Kinase / TRANSFERASE / 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 / 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-35-mediated signaling pathway / nuclear receptor-mediated mineralocorticoid signaling pathway / histone H3Y41 kinase activity / 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 / 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 MHC class II biosynthetic process / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / 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 / regulation of nitric oxide biosynthetic process / Interleukin-12 signaling / positive regulation of epithelial cell apoptotic process / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / positive regulation of natural killer cell proliferation / 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 / growth hormone receptor signaling pathway / positive regulation of tyrosine phosphorylation of STAT protein / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of cardiac muscle cell apoptotic process / 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) / enzyme-linked receptor protein signaling pathway / peptide hormone receptor binding / interleukin-6-mediated signaling pathway / MAPK3 (ERK1) activation / response to amine / Prolactin receptor signaling / platelet-derived growth factor receptor signaling pathway / MAPK1 (ERK2) activation / mesoderm development / positive regulation of interleukin-17 production / response to tumor necrosis factor / signaling receptor activator activity / insulin receptor substrate binding / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of SMAD protein signal transduction / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / cell surface receptor signaling pathway via JAK-STAT / 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 / tumor necrosis factor-mediated signaling pathway / extrinsic apoptotic signaling pathway / actin filament polymerization / positive regulation of T cell proliferation / negative regulation of cytokine production involved in inflammatory response / cellular response to dexamethasone stimulus / post-translational protein modification / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / lipopolysaccharide-mediated signaling pathway / positive regulation of apoptotic signaling pathway / positive regulation of interleukin-1 beta production / erythrocyte differentiation / 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 / : ...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-D7D / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.8 Å
AuthorsHan, S.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.
Authors: Vazquez, M.L. / Kaila, N. / Strohbach, J.W. / Trzupek, J.D. / Brown, M.F. / Flanagan, M.E. / Mitton-Fry, M.J. / Johnson, T.A. / TenBrink, R.E. / Arnold, E.P. / Basak, A. / Heasley, S.E. / ...Authors: Vazquez, M.L. / Kaila, N. / Strohbach, J.W. / Trzupek, J.D. / Brown, M.F. / Flanagan, M.E. / Mitton-Fry, M.J. / Johnson, T.A. / TenBrink, R.E. / Arnold, E.P. / Basak, A. / Heasley, S.E. / Kwon, S. / Langille, J. / Parikh, M.D. / Griffin, S.H. / Casavant, J.M. / Duclos, B.A. / Fenwick, A.E. / Harris, T.M. / Han, S. / Caspers, N. / Dowty, M.E. / Yang, X. / Banker, M.E. / Hegen, M. / Symanowicz, P.T. / Li, L. / Wang, L. / Lin, T.H. / Jussif, J. / Clark, J.D. / Telliez, J.B. / Robinson, R.P. / Unwalla, R.
History
DepositionOct 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Feb 28, 2018Group: Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.3Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)35,1972
Polymers34,8741
Non-polymers3231
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.380, 45.690, 49.010
Angle α, β, γ (deg.)69.03, 72.95, 81.60
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: Protein kinase 2, residues 837-1132
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-D7D / N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide


Mass: 323.414 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H21N5O2S / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 2.08 Å3/Da / Density % sol: 40.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 28% PEG-3350, 0.1 M sodium acetate, 0.1M Hepes, pH 7.5

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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: Oct 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→146 Å / Num. obs: 28123 / % possible obs: 99.9 % / Redundancy: 6.2 % / Biso Wilson estimate: 19.29 Å2 / Net I/σ(I): 18.7

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
SCALAdata scaling
BUSTERphasing
RefinementResolution: 1.8→44 Å / Cor.coef. Fo:Fc: 0.9393 / Cor.coef. Fo:Fc free: 0.9216 / SU R Cruickshank DPI: 0.14 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.139 / SU Rfree Blow DPI: 0.128 / SU Rfree Cruickshank DPI: 0.129
RfactorNum. reflection% reflectionSelection details
Rfree0.2146 1275 5.29 %RANDOM
Rwork0.1755 ---
obs0.1776 24123 89.44 %-
Displacement parametersBiso mean: 24.32 Å2
Baniso -1Baniso -2Baniso -3
1--1.6005 Å22.5921 Å2-4.6108 Å2
2--1.2264 Å21.445 Å2
3---0.3742 Å2
Refine analyzeLuzzati coordinate error obs: 0.207 Å
Refinement stepCycle: 1 / Resolution: 1.8→44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2381 0 22 172 2575
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012477HARMONIC2
X-RAY DIFFRACTIONt_angle_deg13359HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d902SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes70HARMONIC2
X-RAY DIFFRACTIONt_gen_planes364HARMONIC5
X-RAY DIFFRACTIONt_it2477HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.39
X-RAY DIFFRACTIONt_other_torsion17.97
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion300SEMIHARMONIC5
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_contact2879SEMIHARMONIC4
LS refinement shellResolution: 1.78→1.86 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2281 146 4.97 %
Rwork0.1672 2794 -
all0.1703 2940 -
obs--89.6 %
Refinement TLS params.Method: refined / Origin x: -1.5352 Å / Origin y: -0.6461 Å / Origin z: 0.0234 Å
111213212223313233
T-0.0476 Å2-0.0034 Å20.0059 Å2--0.0579 Å2-0.0142 Å2---0.0162 Å2
L0.6786 °2-0.0303 °2-0.4565 °2-0.3291 °20.3069 °2--1.6344 °2
S-0.0128 Å °-0.0023 Å °0.0031 Å °0.019 Å °-0.0017 Å °0.0337 Å °0.0153 Å °-0.0134 Å °0.0145 Å °
Refinement TLS groupSelection details: { A|* }

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