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- PDB-4e6d: JAK2 kinase (JH1 domain) triple mutant in complex with compound 7 -

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Basic information

Entry
Database: PDB / ID: 4e6d
TitleJAK2 kinase (JH1 domain) triple mutant in complex with compound 7
ComponentsTyrosine-protein kinase JAK2
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / JAK2 / kinase / transferase / phosphorylation / 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 / granulocyte macrophage colony-stimulating factor receptor complex ...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 / 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 / acetylcholine receptor binding / interleukin-12-mediated signaling pathway / interleukin-3-mediated signaling pathway / regulation of nitric oxide biosynthetic process / 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 / 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 / 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-0NU / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.22 Å
AuthorsMurray, J.M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors.
Authors: Kulagowski, J.J. / Blair, W. / Bull, R.J. / Chang, C. / Deshmukh, G. / Dyke, H.J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Harrison, T.K. / Hewitt, P.R. / Liimatta, M. / Hurley, C.A. / ...Authors: Kulagowski, J.J. / Blair, W. / Bull, R.J. / Chang, C. / Deshmukh, G. / Dyke, H.J. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Harrison, T.K. / Hewitt, P.R. / Liimatta, M. / Hurley, C.A. / Johnson, A. / Johnson, T. / Kenny, J.R. / Bir Kohli, P. / Maxey, R.J. / Mendonca, R. / Mortara, K. / Murray, J. / Narukulla, R. / Shia, S. / Steffek, M. / Ubhayakar, S. / Ultsch, M. / van Abbema, A. / Ward, S.I. / Waszkowycz, B. / Zak, M.
History
DepositionMar 15, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 30, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 11, 2012Group: Database references
Revision 1.2Mar 1, 2023Group: Database references / Derived calculations
Category: database_2 / pdbx_struct_assembly ...database_2 / pdbx_struct_assembly / pdbx_struct_assembly_gen / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)71,1595
Polymers70,4502
Non-polymers7093
Water5,549308
1
A: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5332
Polymers35,2251
Non-polymers3081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6263
Polymers35,2251
Non-polymers4002
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)111.035, 111.035, 70.575
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 35225.086 Da / Num. of mol.: 2 / Fragment: kinase domain, UNP residues 835-1132 / Mutation: Q853R, Y931F, D939E
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-0NU / 3-[(3R)-3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)piperidin-1-yl]-3-oxopropanenitrile


Mass: 308.338 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H16N6O
#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.: 308 / 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: 3.09 Å3/Da / Density % sol: 60.16 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.025 M Bicine pH 8.5, 0.25 M NaCl, 20% glycerol, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 14, 2009
RadiationMonochromator: Double-crystal, Si(111) / Protocol: SINGLE / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.2→60 Å / Num. all: 42914 / Num. obs: 42879 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.4 % / Biso Wilson estimate: 35 Å2 / Rmerge(I) obs: 0.096 / Net I/σ(I): 14.6
Reflection shellResolution: 2.22→2.34 Å / Redundancy: 7.5 % / Rmerge(I) obs: 0.517 / Mean I/σ(I) obs: 4.2 / Num. unique all: 6212 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
SCALAdata scaling
PHASERphasing
PHENIXdev_991refinement
PDB_EXTRACT3.1data extraction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.22→59.562 Å / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.8825 / SU ML: 0.27 / σ(F): 1.43 / σ(I): 0 / Phase error: 19.08 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2027 2180 5.08 %
Rwork0.1601 --
obs0.1622 42879 99.97 %
all-42914 -
Solvent computationShrinkage radii: 0.73 Å / VDW probe radii: 1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 48.783 Å2 / ksol: 0.379 e/Å3
Displacement parametersBiso max: 142.63 Å2 / Biso mean: 41.6707 Å2 / Biso min: 15.65 Å2
Baniso -1Baniso -2Baniso -3
1-5.014 Å20 Å2-0 Å2
2--5.014 Å20 Å2
3----10.028 Å2
Refinement stepCycle: LAST / Resolution: 2.22→59.562 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4766 0 52 308 5126
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0144883
X-RAY DIFFRACTIONf_angle_d1.456589
X-RAY DIFFRACTIONf_chiral_restr0.105686
X-RAY DIFFRACTIONf_plane_restr0.006891
X-RAY DIFFRACTIONf_dihedral_angle_d16.2311903
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 16 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all
2.22-2.26350.27551390.211425442683
2.2635-2.31620.24541350.193625052640
2.3162-2.37410.28881280.193924972625
2.3741-2.43830.26341450.171525692714
2.4383-2.510.21141420.170125062648
2.51-2.59110.22781340.161725362670
2.5911-2.68370.22321350.15525392674
2.6837-2.79110.21491420.161325082650
2.7911-2.91810.20361470.167525432690
2.9181-3.0720.22331220.169325652687
3.072-3.26440.22611420.163725202662
3.2644-3.51650.20051280.148925532681
3.5165-3.87030.17571260.14925512677
3.8703-4.43020.17541230.135425732696
4.4302-5.58090.16651590.141625552714
5.5809-59.58320.19221330.179426352768
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.98820.13751.74023.2997-0.20726.43220.3311-0.2224-0.6180.0091-0.10980.41360.6438-0.0843-0.16110.2955-0.02730.00770.1445-0.04220.3595-10.0749-53.2879-25.3493
23.12450.20531.41641.830.0314.93770.1618-0.1246-0.5134-0.03030.01380.15420.5589-0.297-0.15040.2687-0.03690.03220.21510.01770.3278-12.0989-50.7993-16.8736
39.47034.16180.30174.64810.51850.9781-0.38881.2146-0.2427-0.58860.4424-0.292-0.38830.2674-0.02450.3921-0.08660.02060.362-0.01590.19063.3189-36.3609-26.9335
42.71450.057-0.15591.9886-0.45144.0186-0.093-0.0823-0.0834-0.00590.05740.00370.0684-0.01640.00930.20370.00350.03070.1243-0.01910.1874-0.7012-40.0605-8.5967
52.63340.349-0.49522.2186-1.44024.2598-0.16970.1438-0.2595-0.18420.0171-0.28580.23260.22490.1340.2129-0.02330.0340.1731-0.01370.253613.1602-42.0876-10.2372
63.639-1.15380.88357.5006-3.02175.24830.01690.0508-0.6836-0.2299-0.2342-0.75360.37980.86990.17580.17560.01830.03570.39610.02860.478922.481-44.4934-7.9824
73.8838-0.73030.11462.22770.1862.7324-0.062-0.12970.4252-0.0040.0067-0.1164-0.52240.12530.09040.3312-0.0551-0.00020.1632-0.02120.25619.2311-27.6248-5.6439
83.79560.78231.13623.92381.64683.80480.05190.12490.13440.0336-0.0043-0.0415-0.03430.486-0.0170.31830.02510.09950.29960.01490.23379.3354-31.333614.1616
96.9808-2.04621.95533.9005-1.61743.88620.0118-0.2545-0.4849-0.17370.0026-0.41270.28960.7575-0.04170.28190.05660.02830.27910.00340.319112.0223-31.892515.3105
105.0705-0.02432.37425.62211.15022.1080.1821-0.07360.5592-0.2888-0.286-0.0823-1.0582-0.02370.22810.362-0.01140.09180.2057-0.01830.36150.8307-17.310412.4316
113.48811.4385-1.78312.2545-1.12992.21330.0039-0.2606-0.0854-0.0504-0.0737-0.1059-0.03490.23570.06790.25390.0243-0.00590.2653-0.00320.1797-3.8726-30.807327.18
122.7589-0.47750.40961.6811-0.53611.59070.12190.0460.389-0.2498-0.0953-0.0064-0.15310.0793-0.01110.3040.03810.05810.1816-0.03420.2452-13.4324-22.477720.1235
133.2142-2.02652.24164.0612-1.88994.89730.68320.2701-0.4553-0.9338-0.24260.53370.8178-0.1326-0.37050.44690.0219-0.1110.2162-0.03190.3502-27.037-33.512115.6261
144.5542-1.72421.39497.58540.27191.4638-0.1504-0.4926-0.07920.09240.19740.5863-0.3346-0.51130.01850.2890.06890.06980.2735-0.06460.2699-26.2584-24.248729.0208
154.90461.627-2.40142.65141.10212.8929-0.3101-0.8755-0.05440.88350.29780.1193-0.42370.0226-0.03950.34350.14450.07120.5152-0.03980.3168-17.6256-26.504239.9784
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 843:868 )A843 - 868
2X-RAY DIFFRACTION2( CHAIN A AND RESID 869:930 )A869 - 930
3X-RAY DIFFRACTION3( CHAIN A AND RESID 931:949 )A931 - 949
4X-RAY DIFFRACTION4( CHAIN A AND RESID 950:1014 )A950 - 1014
5X-RAY DIFFRACTION5( CHAIN A AND RESID 1015:1065 )A1015 - 1065
6X-RAY DIFFRACTION6( CHAIN A AND RESID 1066:1095 )A1066 - 1095
7X-RAY DIFFRACTION7( CHAIN A AND RESID 1096:1132 )A1096 - 1132
8X-RAY DIFFRACTION8( CHAIN B AND RESID 840:868 )B840 - 868
9X-RAY DIFFRACTION9( CHAIN B AND RESID 869:888 )B869 - 888
10X-RAY DIFFRACTION10( CHAIN B AND RESID 889:904 )B889 - 904
11X-RAY DIFFRACTION11( CHAIN B AND RESID 905:970 )B905 - 970
12X-RAY DIFFRACTION12( CHAIN B AND RESID 971:1049 )B971 - 1049
13X-RAY DIFFRACTION13( CHAIN B AND RESID 1050:1095 )B1050 - 1095
14X-RAY DIFFRACTION14( CHAIN B AND RESID 1096:1115 )B1096 - 1115
15X-RAY DIFFRACTION15( CHAIN B AND RESID 1116:1132 )B1116 - 1132

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