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- PDB-10pj: JAK2 kinase (JH1 domain) in complex with povorcitinib -

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Basic information

Entry
Database: PDB / ID: 10pj
TitleJAK2 kinase (JH1 domain) in complex with povorcitinib
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE / Inhibitor / Kinase / 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 / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / regulation of postsynapse to nucleus 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 / symbiont-induced defense-related programmed cell death / positive regulation of growth hormone receptor signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / mammary gland epithelium development / regulation of postsynapse to nucleus 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 / Erythropoietin activates STAT5 / activation of Janus kinase activity / response to interleukin-12 / interleukin-12 receptor binding / interleukin-5-mediated signaling pathway / Erythropoietin activates Phospholipase C gamma (PLCG) / positive regulation of leukocyte proliferation / type 1 angiotensin receptor binding / interleukin-12 receptor complex / interleukin-23 receptor complex / erythropoietin-mediated signaling pathway / post-embryonic hemopoiesis / Interleukin-23 signaling / interleukin-23-mediated signaling pathway / 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 / positive regulation of platelet activation / positive regulation of cell-substrate adhesion / interleukin-3-mediated signaling pathway / acetylcholine receptor binding / Interleukin-12 signaling / cellular response to interleukin-3 / positive regulation of platelet aggregation / Signaling by Leptin / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / regulation of nitric oxide biosynthetic process / positive regulation of epithelial cell apoptotic process / axon regeneration / response to hydroperoxide / regulation of receptor signaling pathway via JAK-STAT / intrinsic apoptotic signaling pathway in response to oxidative stress / growth hormone receptor signaling pathway / positive regulation of tyrosine phosphorylation of STAT protein / extrinsic component of plasma membrane / negative regulation of cell-cell adhesion / Interleukin-20 family signaling / extrinsic component of cytoplasmic side of plasma membrane / Interleukin-6 signaling / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / interleukin-6-mediated signaling pathway / enzyme-linked receptor protein signaling pathway / peptide hormone receptor binding / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Prolactin receptor signaling / platelet-derived growth factor receptor signaling pathway / positive regulation of interleukin-17 production / mesoderm development / positive regulation of natural killer cell proliferation / signaling receptor activator activity / positive regulation of SMAD protein signal transduction / negative regulation of cardiac muscle cell apoptotic process / Interleukin-3, Interleukin-5 and GM-CSF signaling / insulin receptor substrate binding / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / Interleukin receptor SHC signaling / cellular response to dexamethasone stimulus / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Growth hormone receptor signaling / cell surface receptor signaling pathway via JAK-STAT / phosphatidylinositol 3-kinase binding / Erythropoietin activates RAS / positive regulation of vascular associated smooth muscle cell proliferation / extrinsic apoptotic signaling pathway / Signaling by CSF3 (G-CSF) / negative regulation of protein localization to chromatin / actin filament polymerization / negative regulation of cytokine production involved in inflammatory response / positive regulation of T cell proliferation / post-translational protein modification / lipopolysaccharide-mediated signaling pathway / SH2 domain binding / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / endosome lumen / tumor necrosis factor-mediated signaling pathway / positive regulation of interleukin-1 beta production / erythrocyte differentiation / positive regulation of receptor signaling pathway via JAK-STAT / non-specific protein-tyrosine kinase
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 / 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
: / MALONIC ACID / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.59 Å
AuthorsEpling, L.B. / Fenalti, G.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2026
Title: Discovery of the Orally Bioavailable Isoform Selective Janus Kinase 1 (JAK1) Compound Povorcitinib (INCB054707) for the Treatment of Inflammatory and Autoimmune Diseases.
Authors: Zhuo, J. / Li, Y.L. / Qian, D.Q. / Burns, D.M. / Mei, S. / Rafalski, M. / Xu, M. / Cao, G. / Pan, Y. / Jia, Z. / Jalluri, R. / Epling, L.B. / Fenalti, G. / Deller, M.C. / Procak, J. / ...Authors: Zhuo, J. / Li, Y.L. / Qian, D.Q. / Burns, D.M. / Mei, S. / Rafalski, M. / Xu, M. / Cao, G. / Pan, Y. / Jia, Z. / Jalluri, R. / Epling, L.B. / Fenalti, G. / Deller, M.C. / Procak, J. / Covington, M. / He, X. / Collins, R. / Stubbs, M. / Burke, K. / Oliver, J. / Margulis, A. / Boer, J. / Wynn, R. / Scherle, P. / Diamond, S. / Newton, R. / Zhang, Y. / Metcalf, B. / Yao, W.
History
DepositionJan 30, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2026Provider: repository / Type: Initial release
Revision 1.1Jun 17, 2026Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)75,6565
Polymers74,5372
Non-polymers1,1193
Water12,178676
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,8803
Polymers37,2681
Non-polymers6122
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7762
Polymers37,2681
Non-polymers5071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)99.610, 69.132, 110.326
Angle α, β, γ (deg.)90.000, 99.519, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+z)
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z+1/2
#4: -x+1/2,y+1/2,-z+1/2
Components on special symmetry positions
IDModelComponents
11B-2189-

HOH

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Components

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


Mass: 37268.285 Da / Num. of mol.: 2 / Fragment: JH1 domain
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-MLA / MALONIC ACID / DICARBOXYLIC ACID C3 / PROPANEDIOLIC ACID / METHANEDICARBOXYLIC ACID


Mass: 104.061 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H4O4
#3: Chemical ChemComp-A1C68 / 4-{3-(cyanomethyl)-3-[(4M)-3',5'-dimethyl-1H,1'H-[4,4'-bipyrazol]-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(2S)-1,1,1-trifluoropropan-2-yl]benzamide


Mass: 507.459 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H22F5N7O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 676 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.51 Å3/Da / Density % sol: 51.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100 mM MD - Buffer System 6 pH 8.0, 1.4 M Na2-Malonate pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 0.97626 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 13, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 1.59→33.78 Å / Num. obs: 93036 / % possible obs: 93.2 % / Redundancy: 7 % / Biso Wilson estimate: 13.54 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.06 / Rrim(I) all: 0.12 / Net I/σ(I): 9
Reflection shellResolution: 1.59→1.72 Å / Redundancy: 7.3 % / Rmerge(I) obs: 0.65 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 9767 / CC1/2: 0.92 / Rpim(I) all: 0.39 / Rrim(I) all: 0.76 / % possible all: 98.5

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Processing

Software
NameVersionClassification
PHENIX1.21.2_5419refinement
autoPROCdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.59→33.78 Å / SU ML: 0.1921 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.1772
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2307 4602 4.96 %
Rwork0.2006 88221 -
obs0.2022 92823 92.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.52 Å2
Refinement stepCycle: LAST / Resolution: 1.59→33.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4964 0 79 676 5719
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01355427
X-RAY DIFFRACTIONf_angle_d1.47027398
X-RAY DIFFRACTIONf_chiral_restr0.0867772
X-RAY DIFFRACTIONf_plane_restr0.0165948
X-RAY DIFFRACTIONf_dihedral_angle_d6.5859841
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.59-1.60.3161270.26383057X-RAY DIFFRACTION98
1.6-1.620.28181840.2573126X-RAY DIFFRACTION98.92
1.62-1.640.2921790.23733071X-RAY DIFFRACTION97.95
1.64-1.660.23841460.23523111X-RAY DIFFRACTION98.88
1.66-1.690.23361660.23393100X-RAY DIFFRACTION98.14
1.69-1.710.25931620.23773114X-RAY DIFFRACTION99.42
1.71-1.730.29621080.26082109X-RAY DIFFRACTION66.28
1.73-1.760.3321740.23473075X-RAY DIFFRACTION99.33
1.76-1.790.24011750.23653113X-RAY DIFFRACTION98.74
1.79-1.820.29261370.22313173X-RAY DIFFRACTION99.04
1.82-1.850.26071740.2123092X-RAY DIFFRACTION99.15
1.85-1.880.23971650.21383097X-RAY DIFFRACTION98.64
1.88-1.910.23561100.20782121X-RAY DIFFRACTION80.17
1.92-1.960.26271140.20472057X-RAY DIFFRACTION73.79
1.96-20.25011710.20473086X-RAY DIFFRACTION98.79
2-2.050.21721430.19963072X-RAY DIFFRACTION96.81
2.05-2.10.22221070.2042194X-RAY DIFFRACTION69.39
2.1-2.150.24131680.19323134X-RAY DIFFRACTION99.55
2.15-2.220.20261630.19493156X-RAY DIFFRACTION99.4
2.22-2.290.22311230.19172685X-RAY DIFFRACTION84.45
2.29-2.370.23061570.20373191X-RAY DIFFRACTION99.85
2.37-2.470.25891540.20693155X-RAY DIFFRACTION99.85
2.47-2.580.24851550.20833172X-RAY DIFFRACTION99.91
2.58-2.710.23071380.20492659X-RAY DIFFRACTION83.94
2.71-2.880.23221860.20843124X-RAY DIFFRACTION99.82
2.88-3.110.22691600.20273198X-RAY DIFFRACTION99.76
3.11-3.420.22141590.17863171X-RAY DIFFRACTION99.64
3.42-3.880.18081510.162458X-RAY DIFFRACTION82.41
3.92-4.920.18471630.15483177X-RAY DIFFRACTION99.29
4.93-33.780.22171830.21363173X-RAY DIFFRACTION97.36

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