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- PDB-4e4l: JAK1 kinase (JH1 domain) in complex with compound 30 -

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Basic information

Entry
Database: PDB / ID: 4e4l
TitleJAK1 kinase (JH1 domain) in complex with compound 30
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / o-phosphotyrosine / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / positive regulation of homotypic cell-cell adhesion / CCR5 chemokine receptor binding / T-helper 17 cell lineage commitment / type III interferon-mediated signaling pathway / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway ...protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / positive regulation of homotypic cell-cell adhesion / CCR5 chemokine receptor binding / T-helper 17 cell lineage commitment / type III interferon-mediated signaling pathway / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / interleukin-15-mediated signaling pathway / Interleukin-15 signaling / Interleukin-12 signaling / Interleukin-35 Signalling / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-2 signaling / growth hormone receptor binding / Other interleukin signaling / IFNG signaling activates MAPKs / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / interleukin-6-mediated signaling pathway / positive regulation of sprouting angiogenesis / MAPK3 (ERK1) activation / Interleukin-10 signaling / MAPK1 (ERK2) activation / cell surface receptor signaling pathway via JAK-STAT / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / type II interferon-mediated signaling pathway / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / extrinsic component of cytoplasmic side of plasma membrane / Interleukin-7 signaling / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Inactivation of CSF3 (G-CSF) signaling / cytoplasmic side of plasma membrane / ISG15 antiviral mechanism / cellular response to virus / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / Interferon gamma signaling / Interferon alpha/beta signaling / RAF/MAP kinase cascade / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / response to antibiotic / protein phosphorylation / focal adhesion / ubiquitin protein ligase binding / SARS-CoV-2 activates/modulates innate and adaptive immune responses / ATP binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak1 / 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 ...Tyrosine-protein kinase, non-receptor Jak1 / 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 / 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. / 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-0NH / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsEigenbrot, C.
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 13, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 30, 2012Provider: repository / Type: Initial release
Revision 1.1Jul 11, 2012Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK1
B: Tyrosine-protein kinase JAK1
E: Tyrosine-protein kinase JAK1
D: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,3208
Polymers138,9864
Non-polymers1,3344
Water9,944552
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4133
Polymers34,7471
Non-polymers6672
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0802
Polymers34,7471
Non-polymers3331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
E: Tyrosine-protein kinase JAK1


Theoretical massNumber of molelcules
Total (without water)34,7471
Polymers34,7471
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0802
Polymers34,7471
Non-polymers3331
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.837, 171.759, 87.821
Angle α, β, γ (deg.)90.00, 92.15, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.999969, 0.000661, 0.007849), (-0.00061, -0.999979, 0.006455), (0.007853, 0.00645, 0.999948)-22.32482, 109.50098, -0.14042
3given(-0.999925, 0.011919, 0.002638), (-0.011902, -0.999908, 0.006509), (0.002715, 0.006477, 0.999975)-19.593, 111.16192, 43.55382
4given(0.99983, -0.017982, 0.004028), (0.017992, 0.999835, -0.00261), (-0.003981, 0.002682, 0.999988)-0.99012, -0.9524, 43.73676

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Components

#1: Protein
Tyrosine-protein kinase JAK1 / Janus kinase 1 / JAK-1


Mass: 34746.594 Da / Num. of mol.: 4 / Fragment: protein kinase domain JH1, UNP residues 854-1154
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, JAK1A, JAK1B / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-0NH / 1-[4-methyl-1-(methylsulfonyl)piperidin-4-yl]-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine


Mass: 333.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H19N5O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 552 / 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: 2.32 Å3/Da / Density % sol: 47.05 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: MES pH 5.5 30% PEG6000, VAPOR DIFFUSION, SITTING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 30, 2010
RadiationMonochromator: double-crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 80512 / Num. obs: 80512 / % possible obs: 94.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -2 / Redundancy: 3.2 % / Biso Wilson estimate: 26 Å2 / Rsym value: 0.07 / Net I/σ(I): 15
Reflection shellResolution: 2→2.07 Å / Mean I/σ(I) obs: 2.6 / Rsym value: 0.432 / % possible all: 90.3

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
REFMAC5.6.0117refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→50 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.929 / SU B: 7.873 / SU ML: 0.118 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): -2 / ESU R: 0.204 / ESU R Free: 0.17 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22814 3725 4.6 %RANDOM
Rwork0.18957 ---
all0.19 80512 --
obs0.19138 76787 94.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.25 Å2
Baniso -1Baniso -2Baniso -3
1--0.65 Å2-0 Å20.12 Å2
2--0.19 Å2-0 Å2
3---0.47 Å2
Refinement stepCycle: LAST / Resolution: 2→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9166 0 92 552 9810
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.029623
X-RAY DIFFRACTIONr_bond_other_d0.0060.026716
X-RAY DIFFRACTIONr_angle_refined_deg1.2521.99813012
X-RAY DIFFRACTIONr_angle_other_deg0.844316393
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.79751145
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.66224.315438
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.401151785
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.5731556
X-RAY DIFFRACTIONr_chiral_restr0.1160.21375
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02110515
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021909
LS refinement shellResolution: 2.001→2.109 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.277 536 -
Rwork0.23 10443 -
obs--89.26 %
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)
11.09750.487-0.08471.0709-0.50982.12520.0248-0.12070.04660.179-0.01010.204-0.006-0.0588-0.01470.03970.00730.03790.04570.0070.0573-24.572926.51692.5777
21.2112-0.1363-0.06011.5988-0.15130.7689-0.05590.02040.1015-0.20060.0781-0.09360.01630.0498-0.02220.0297-0.01160.00660.02250.00540.0209-8.793734.4263-15.9976
31.11730.19930.38881.1880.73772.29170.0191-0.1355-0.03090.2230.013-0.1980.1769-0.032-0.03210.04890.0019-0.02420.02560.00280.07532.512682.90952.2067
41.21070.05480.25290.952-0.02360.6813-0.02240.002-0.058-0.09230.0848-0.0062-0.0094-0.011-0.06240.0157-0.00480.00770.0113-0.00230.0272-13.602774.9941-16.2996
50.95960.21460.72541.02380.84492.4849-0.0666-0.0147-0.16810.13190.0447-0.12160.0952-0.03750.02190.02890.00990.00930.02670.01370.09116.409784.3037-41.427
61.1804-0.04630.00212.1818-0.09230.6178-0.08440.0819-0.126-0.31010.13030.14870.0370.0042-0.04590.068-0.0118-0.00670.0257-0.00130.0559-10.083376.445-60.0784
71.139-0.0603-0.08261.0136-0.48911.9737-0.02370.05450.05530.14670.02870.2486-0.0471-0.0861-0.0050.0238-0.0030.03660.01990.00530.0737-23.167527.9389-41.2434
81.0271-0.3261-0.282.12420.06590.80220.05780.16320.1426-0.25740.0338-0.17-0.05-0.0969-0.09170.03390.00550.02640.06550.02840.0331-6.911835.4012-59.9013
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A865 - 959
2X-RAY DIFFRACTION2A960 - 1154
3X-RAY DIFFRACTION3B864 - 959
4X-RAY DIFFRACTION4B960 - 1154
5X-RAY DIFFRACTION5D864 - 959
6X-RAY DIFFRACTION6D960 - 1154
7X-RAY DIFFRACTION7E864 - 959
8X-RAY DIFFRACTION8E960 - 1154

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