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- PDB-8s85: Crystal structure of JAK1 JH1 domain in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 8s85
TitleCrystal structure of JAK1 JH1 domain in complex with an inhibitor
ComponentsTyrosine-protein kinase JAK1
KeywordsSIGNALING PROTEIN / Kinase / JAK1 / Inhibitor
Function / homology
Function and homology information


type III interferon-mediated signaling pathway / protein localization to cell-cell junction / interleukin-10-mediated signaling pathway / CCR5 chemokine receptor binding / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway ...type III interferon-mediated signaling pathway / protein localization to cell-cell junction / interleukin-10-mediated signaling pathway / CCR5 chemokine receptor binding / interleukin-11-mediated signaling pathway / T-helper 17 cell lineage commitment / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-7-mediated signaling pathway / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / positive regulation of homotypic cell-cell adhesion / interleukin-2-mediated signaling pathway / interleukin-15-mediated signaling pathway / Interleukin-12 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-27 signaling / Interleukin-35 Signalling / growth hormone receptor binding / Interleukin-15 signaling / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / Other interleukin signaling / Interleukin-20 family signaling / Interleukin-6 signaling / type I interferon-mediated signaling pathway / IFNG signaling activates MAPKs / MAPK3 (ERK1) activation / interleukin-6-mediated signaling pathway / positive regulation of sprouting angiogenesis / MAPK1 (ERK2) activation / Interleukin-10 signaling / Regulation of IFNA/IFNB signaling / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / Interleukin receptor SHC signaling / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / Interleukin-7 signaling / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cytokine-mediated signaling pathway / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / cellular response to virus / positive regulation of protein localization to nucleus / ISG15 antiviral mechanism / cytoplasmic side of plasma membrane / Interferon gamma signaling / Interferon alpha/beta signaling / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / Interleukin-4 and Interleukin-13 signaling / Potential therapeutics for SARS / cell differentiation / cytoskeleton / receptor complex / 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 / : / SH2 domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like 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 / : / SH2 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
: / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsFlower, T.F. / Lopez-Ramos, M. / Geney, R. / Jestel, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2024
Title: Design of a potent and selective dual JAK1/TYK2 inhibitor.
Authors: Mammoliti, O. / Menet, C. / Cottereaux, C. / Blanc, J. / De Blieck, A. / Coti, G. / Geney, R. / Oste, L. / Ostyn, K. / Palisse, A. / Quinton, E. / Schmitt, B. / Borgonovi, M. / Parent, I. / ...Authors: Mammoliti, O. / Menet, C. / Cottereaux, C. / Blanc, J. / De Blieck, A. / Coti, G. / Geney, R. / Oste, L. / Ostyn, K. / Palisse, A. / Quinton, E. / Schmitt, B. / Borgonovi, M. / Parent, I. / Jagerschmidt, C. / De Vos, S. / Vayssiere, B. / Lopez-Ramos, M. / Shoji, K. / Brys, R. / Amantini, D. / Galien, R. / Joannesse, C.
History
DepositionMar 5, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,0957
Polymers69,4932
Non-polymers6025
Water7,891438
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0825
Polymers34,7471
Non-polymers3354
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0132
Polymers34,7471
Non-polymers2661
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)43.038, 174.030, 44.893
Angle α, β, γ (deg.)90.00, 94.50, 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.: 2
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-A1H5R / ~{N}-(2-ethylphenyl)-~{N},1-dimethyl-imidazo[4,5-c]pyridin-6-amine


Mass: 266.341 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18N4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 438 / 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: 2.41 Å3/Da / Density % sol: 49 %
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

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 26, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.75→87.01 Å / Num. obs: 60553 / % possible obs: 96.2 % / Redundancy: 3.5 % / Rrim(I) all: 0.059 / Rsym value: 0.05 / Net I/σ(I): 17.8
Reflection shellResolution: 1.75→1.82 Å / Num. unique obs: 6840 / Rrim(I) all: 0.657 / Rsym value: 0.547

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Processing

Software
NameVersionClassification
REFMAC5refinement
XSCALEdata scaling
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→87.01 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.926 / SU B: 6.095 / SU ML: 0.109 / Cross valid method: THROUGHOUT / ESU R: 0.133 / ESU R Free: 0.13 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2496 2941 4.6 %RANDOM
Rwork0.20791 ---
obs0.20988 60553 96.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 35.589 Å2
Baniso -1Baniso -2Baniso -3
1--0.93 Å20 Å20.31 Å2
2---0.56 Å20 Å2
3---1.54 Å2
Refinement stepCycle: LAST / Resolution: 1.75→87.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4682 0 43 438 5163
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0224764
X-RAY DIFFRACTIONr_bond_other_d0.0020.024292
X-RAY DIFFRACTIONr_angle_refined_deg1.331.9886461
X-RAY DIFFRACTIONr_angle_other_deg1.28539983
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0835590
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.92524.307202
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.2915831
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5341523
X-RAY DIFFRACTIONr_chiral_restr0.0760.2701
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.025288
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02945
X-RAY DIFFRACTIONr_nbd_refined0.1860.2913
X-RAY DIFFRACTIONr_nbd_other0.1670.24109
X-RAY DIFFRACTIONr_nbtor_refined0.1650.22302
X-RAY DIFFRACTIONr_nbtor_other0.0690.22470
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1220.2301
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined0.0170.21
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2450.28
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2070.265
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1330.231
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.0360.22
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.92922927
X-RAY DIFFRACTIONr_mcbond_other0.48421184
X-RAY DIFFRACTIONr_mcangle_it2.84734726
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.03541898
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.58161735
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.751→1.796 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.365 191 -
Rwork0.296 4327 -
obs--92.07 %
Refinement TLS params.

Method: refined / Origin x: 0 Å / Refine-ID: X-RAY DIFFRACTION

IDL11 esd (°2)L12 esd (°2)L13 esd (°2)L22 esd (°2)L23 esd (°2)L33 esd (°2)S11 esd (Å °)S12 esd (Å °)S13 esd (Å °)S21 esd (Å °)S22 esd (Å °)S23 esd (Å °)S31 esd (Å °)S32 esd (Å °)S33 esd (Å °)T11 (Å2)T11 esd (Å2)T12 esd (Å2)T13 esd (Å2)T22 esd (Å2)T23 esd (Å2)T33 esd (Å2)Origin y (Å)Origin z (Å)
12.8108-0.55111.48430.7998-1.31045.04250.11690.1604-0.4708-0.21250.06650.15390.2698-0.0462-0.1833-2.5090.0997-0.0166-0.00770.0815-0.04750.1415-3.1959.39
25.0861-0.0281.0751.7646-0.33511.9580.1034-0.2643-0.9130.15450.07110.03180.1421-0.0603-0.174616.3650.1031-0.00560.00030.06140.04280.184212.77851.395
34.38480.4968-0.71051.7570.38975.3949-0.09020.22760.1437-0.35440.0935-0.2291-0.16920.1074-0.0034-2.7490.1152-0.02190.03170.0654-0.00160.04624.7432.945
45.80911.6121-1.21233.05740.06261.78170.3396-0.64591.09080.3049-0.14790.5443-0.19710.112-0.191616.1230.131-0.04540.07230.1436-0.11230.2298.57510.139
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A867 - 959
2X-RAY DIFFRACTION2A961 - 2000
3X-RAY DIFFRACTION3B867 - 959
4X-RAY DIFFRACTION4B961 - 2000

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