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- PDB-4ehz: The Jak1 kinase domain in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 4ehz
TitleThe Jak1 kinase domain in complex with inhibitor
ComponentsTyrosine-protein kinase JAK1
KeywordsTransferase/Transferase Inhibitor / kinase / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / type III interferon-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of homotypic cell-cell adhesion / 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 / CCR5 chemokine receptor binding / type III interferon-mediated signaling pathway / T-helper 17 cell lineage commitment / positive regulation of homotypic cell-cell adhesion / 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-mediated signaling pathway / type I interferon-mediated signaling pathway / Interleukin-6 signaling / 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 / protein phosphorylation / response to antibiotic / 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-JAK / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.174 Å
AuthorsLupardus, P.J. / Steffek, M.
CitationJournal: J.Med.Chem. / Year: 2012
Title: Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.
Authors: Zak, M. / Mendonca, R. / Balazs, M. / Barrett, K. / Bergeron, P. / Blair, W.S. / Chang, C. / Deshmukh, G. / Devoss, J. / Dragovich, P.S. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Gradl, ...Authors: Zak, M. / Mendonca, R. / Balazs, M. / Barrett, K. / Bergeron, P. / Blair, W.S. / Chang, C. / Deshmukh, G. / Devoss, J. / Dragovich, P.S. / Eigenbrot, C. / Ghilardi, N. / Gibbons, P. / Gradl, S. / Hamman, C. / Hanan, E.J. / Harstad, E. / Hewitt, P.R. / Hurley, C.A. / Jin, T. / Johnson, A. / Johnson, T. / Kenny, J.R. / Koehler, M.F. / Bir Kohli, P. / Kulagowski, J.J. / Labadie, S. / Liao, J. / Liimatta, M. / Lin, Z. / Lupardus, P.J. / Maxey, R.J. / Murray, J.M. / Pulk, R. / Rodriguez, M. / Savage, S. / Shia, S. / Steffek, M. / Ubhayakar, S. / Ultsch, M. / van Abbema, A. / Ward, S.I. / Xiao, L. / Xiao, Y.
History
DepositionApr 4, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 4, 2012Provider: repository / Type: Initial release
Revision 1.1Aug 29, 2012Group: Database references
Revision 1.2Jan 23, 2013Group: 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
C: Tyrosine-protein kinase JAK1
D: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)140,75220
Polymers138,9864
Non-polymers1,76616
Water10,106561
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3127
Polymers34,7471
Non-polymers5666
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0643
Polymers34,7471
Non-polymers3172
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2506
Polymers34,7471
Non-polymers5045
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1264
Polymers34,7471
Non-polymers3793
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.712, 172.175, 88.035
Angle α, β, γ (deg.)90.00, 92.28, 90.00
Int Tables number4
Space group name H-MP1211

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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: kinase domain, 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-JAK / 2-methyl-1-(piperidin-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine


Mass: 255.318 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H17N5
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 561 / 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: 2.33 Å3/Da / Density % sol: 47.15 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1 M MES pH 5-6 and 25-35% PEG 6000, VAPOR DIFFUSION, SITTING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.17→30 Å / Num. obs: 63591 / % possible obs: 95.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.5 % / Biso Wilson estimate: 23.75 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 13.5
Reflection shellResolution: 2.17→2.25 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.373 / Mean I/σ(I) obs: 3.2 / % possible all: 87.6

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Processing

Software
NameVersionClassification
BOSdata collection
PHASERphasing
PHENIX(phenix.refine: 1.7_648)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.174→30 Å / SU ML: 0.31 / σ(F): 0 / Phase error: 24.01 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2287 3033 5.03 %Random
Rwork0.1712 ---
obs0.1741 60351 90.65 %-
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 28.234 Å2 / ksol: 0.332 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--2.3668 Å20 Å20.6913 Å2
2--1.5727 Å2-0 Å2
3---0.794 Å2
Refinement stepCycle: LAST / Resolution: 2.174→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9239 0 124 561 9924
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0079581
X-RAY DIFFRACTIONf_angle_d1.08512905
X-RAY DIFFRACTIONf_dihedral_angle_d14.8393641
X-RAY DIFFRACTIONf_chiral_restr0.071372
X-RAY DIFFRACTIONf_plane_restr0.0041636
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.174-2.20780.24211070.18962115X-RAY DIFFRACTION73
2.2078-2.2440.30731110.19472301X-RAY DIFFRACTION79
2.244-2.28270.30661030.20512327X-RAY DIFFRACTION81
2.2827-2.32410.2981290.20322336X-RAY DIFFRACTION82
2.3241-2.36880.28411300.20422450X-RAY DIFFRACTION84
2.3688-2.41720.27131200.2012382X-RAY DIFFRACTION85
2.4172-2.46970.28391400.19722499X-RAY DIFFRACTION87
2.4697-2.52710.27811320.18992541X-RAY DIFFRACTION88
2.5271-2.59030.28221490.18712519X-RAY DIFFRACTION90
2.5903-2.66030.22531340.17182654X-RAY DIFFRACTION91
2.6603-2.73850.23911370.17182600X-RAY DIFFRACTION92
2.7385-2.82680.24241630.17182680X-RAY DIFFRACTION93
2.8268-2.92780.23661320.17372695X-RAY DIFFRACTION95
2.9278-3.04490.2091340.17212734X-RAY DIFFRACTION94
3.0449-3.18330.23041260.18272726X-RAY DIFFRACTION96
3.1833-3.3510.24021690.1872764X-RAY DIFFRACTION96
3.351-3.56060.25371560.17092831X-RAY DIFFRACTION97
3.5606-3.8350.22041540.1552792X-RAY DIFFRACTION98
3.835-4.220.17541500.13872824X-RAY DIFFRACTION98
4.22-4.82850.16931520.13342851X-RAY DIFFRACTION99
4.8285-6.07510.22631480.17842854X-RAY DIFFRACTION99
6.0751-300.18391570.17042843X-RAY DIFFRACTION98
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)
10.0059-0.0024-0.00550.0068-0.00770.0221-0.0045-0.00530.0134-0.00550.01340.01140.0052-0.0184-0.00620.0352-0.0054-0.01580.076-0.01170.0718-20.839867.5665-6.3064
20.0992-0.03230.06180.0446-0.02560.0613-0.02120.013-0.03080.00120.03840.0224-0.0133-0.0274-0.00290.0673-0.00490.00220.0739-0.00230.06731.629558.92664.5368
30.03770.00540.01320.003-0.00350.0235-0.0002-0.0224-0.05810.03880.0316-0.024-0.00950.0105-0.01020.0620.02-0.00840.00480.00570.045114.493347.150418.3944
40.21360.0245-0.06580.1429-0.04890.0312-0.0125-0.0639-0.0003-0.04930.0127-0.0170.03340.02590.00590.08150.0059-0.00080.0712-0.00460.057519.10532.92444.1403
50.010.003-0.00150.00380.00290.01090.0375-0.01460.05430.01940.01620.0278-0.03720.0033-0.01420.06770.01490.0733-0.0162-0.05640.00245.70614.862818.2903
60.0128-0.01840.00560.0252-0.0110.05190.01520.0055-0.0143-0.00620.03260.02250.008-0.0257-0.02650.0547-0.0052-0.00780.08870.01060.07664.948756.3765-38.6066
70.1191-0.02630.02410.03970.00290.11950.0389-0.0199-0.069-0.00340.0311-0.00330.00670.0057-0.03340.08470.0037-0.01680.0506-0.00340.081218.885745.8962-24.9843
80.1528-0.0629-0.04150.0647-0.00380.1657-0.05340.03550.050.00310.0275-0.03930.0265-0.01320.01420.0666-0.0065-0.00770.0759-0.01380.077220.60761.6007-39.7158
90.03210.0003-0.0040.00220.00660.006-0.0168-0.02330.06380.01940.0278-0.00030.00070.0049-0.0007-0.00750.09340.0151-0.0992-0.11210.01127.564413.6259-25.5267
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resseq 858:871)
2X-RAY DIFFRACTION2chain 'A' and (resseq 872:1033)
3X-RAY DIFFRACTION3chain 'A' and (resseq 1036:1154)
4X-RAY DIFFRACTION4chain 'B' and (resseq 865:1033)
5X-RAY DIFFRACTION5chain 'B' and (resseq 1036:1154)
6X-RAY DIFFRACTION6chain 'C' and (resseq 866:1041)
7X-RAY DIFFRACTION7chain 'C' and (resseq 1042:1154)
8X-RAY DIFFRACTION8chain 'D' and (resseq 865:1033)
9X-RAY DIFFRACTION9chain 'D' and (resseq 1036:1154)

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