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- PDB-4ei4: JAK1 kinase (JH1 domain) in complex with compound 20 -

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Basic information

Entry
Database: PDB / ID: 4ei4
TitleJAK1 kinase (JH1 domain) in complex with compound 20
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / phospho-transfer catalyst / 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-0Q2 / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.22 Å
AuthorsEigenbrot, C. / 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 1.1Jan 2, 2013Group: Database references
Revision 1.2Jan 23, 2013Group: Database references
Revision 1.3Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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
Revision 1.5Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)70,0344
Polymers69,4932
Non-polymers5412
Water2,090116
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0172
Polymers34,7471
Non-polymers2701
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0172
Polymers34,7471
Non-polymers2701
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.755, 173.322, 44.595
Angle α, β, γ (deg.)90.00, 94.27, 90.00
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A850 - 1160
2114B850 - 1160

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Components

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


Mass: 34746.594 Da / Num. of mol.: 2 / Fragment: JH1 (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-0Q2 / (1R,3R)-3-(2-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(8H)-yl)cyclohexanol


Mass: 270.330 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C15H18N4O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.37 Å3/Da / Density % sol: 48.12 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: PEG 6000, pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 30, 2010
RadiationMonochromator: SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.22→50 Å / Num. all: 32187 / Num. obs: 32187 / % possible obs: 99.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -2 / Redundancy: 3.2 % / Biso Wilson estimate: 40 Å2 / Rsym value: 0.069 / Net I/σ(I): 15
Reflection shellResolution: 2.22→2.3 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 2.7 / Rsym value: 0.383 / % possible all: 99.8

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 2B7A

2b7a


Resolution: 2.22→50 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.931 / SU B: 13.363 / SU ML: 0.167 / Cross valid method: THROUGHOUT / ESU R: 0.3 / ESU R Free: 0.216 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23941 1513 4.8 %RANDOM
Rwork0.20035 ---
all0.20217 30234 --
obs0.20217 30234 99.71 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 40.269 Å2
Baniso -1Baniso -2Baniso -3
1--0.96 Å20 Å2-0.53 Å2
2--0.74 Å20 Å2
3---0.13 Å2
Refinement stepCycle: LAST / Resolution: 2.22→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4661 0 40 116 4817
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224807
X-RAY DIFFRACTIONr_bond_other_d0.0060.023354
X-RAY DIFFRACTIONr_angle_refined_deg1.1351.996486
X-RAY DIFFRACTIONr_angle_other_deg0.82938193
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6935567
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.65924.389221
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.44315894
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.7691526
X-RAY DIFFRACTIONr_chiral_restr0.0610.2691
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025203
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02931
X-RAY DIFFRACTIONr_nbd_refined0.1950.2914
X-RAY DIFFRACTIONr_nbd_other0.1890.23360
X-RAY DIFFRACTIONr_nbtor_refined0.1750.22290
X-RAY DIFFRACTIONr_nbtor_other0.0810.22355
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1550.2128
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1840.212
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2220.243
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2080.211
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.1092.52997
X-RAY DIFFRACTIONr_mcbond_other0.7852.51151
X-RAY DIFFRACTIONr_mcangle_it3.94754617
X-RAY DIFFRACTIONr_scbond_it3.1972.52141
X-RAY DIFFRACTIONr_scangle_it4.48151869
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Number: 3910 / Refine-ID: X-RAY DIFFRACTION

TypeRms dev position (Å)Weight position
medium positional0.350.5
medium thermal0.72
LS refinement shellResolution: 2.22→2.34 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.267 233 -
Rwork0.243 4394 -
obs--99.91 %
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)
11.4564-0.06160.81410.4368-0.74392.1202-0.00010.0653-0.2324-0.06420.05990.12630.1249-0.0025-0.0598-0.0451-0.0337-0.0103-0.0224-0.05630.0373-6.428360.5524-3.4399
21.354-0.03370.14870.9536-0.19860.5502-0.0008-0.0513-0.17970.08250.05350.0429-0.0151-0.0049-0.0528-0.0351-0.01920.0119-0.0505-0.01020.005112.880451.18316.0977
31.9928-0.0943-0.12061.00470.14471.46830.06180.07540.0154-0.15860.005-0.1440.02260.0513-0.0668-0.0390.00640.0043-0.03580.0004-0.056824.64032.8254-3.0362
41.59140.1585-0.11371.25630.17530.65090.0316-0.22370.19960.0450.03420.1032-0.01160.0218-0.0658-0.0504-0.015-0.0032-0.0072-0.0414-0.06228.381510.368815.5699
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A853 - 959
2X-RAY DIFFRACTION2A960 - 2000
3X-RAY DIFFRACTION3B853 - 959
4X-RAY DIFFRACTION4B960 - 2000

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