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- PDB-6smb: Human jak1 kinase domain in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 6smb
TitleHuman jak1 kinase domain in complex with inhibitor
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE / Janus Kinase 1 kinase domain (JAK1)
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
Chem-LKQ / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.04 Å
AuthorsRead, J.A. / Steuber, H.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.
Authors: Su, Q. / Banks, E. / Bebernitz, G. / Bell, K. / Borenstein, C.F. / Chen, H. / Chuaqui, C.E. / Deng, N. / Ferguson, A.D. / Kawatkar, S. / Grimster, N.P. / Ruston, L. / Lyne, P.D. / Read, J.A. ...Authors: Su, Q. / Banks, E. / Bebernitz, G. / Bell, K. / Borenstein, C.F. / Chen, H. / Chuaqui, C.E. / Deng, N. / Ferguson, A.D. / Kawatkar, S. / Grimster, N.P. / Ruston, L. / Lyne, P.D. / Read, J.A. / Peng, X. / Pei, X. / Fawell, S. / Tang, Z. / Throner, S. / Vasbinder, M.M. / Wang, H. / Winter-Holt, J. / Woessner, R. / Wu, A. / Yang, W. / Zinda, M. / Kettle, J.G.
History
DepositionAug 21, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 13, 2020Group: Database references / Category: citation / citation_author
Item: _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Nov 20, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification

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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)70,3164
Polymers69,3792
Non-polymers9372
Water3,801211
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1582
Polymers34,6901
Non-polymers4691
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1582
Polymers34,6901
Non-polymers4691
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.553, 171.567, 44.383
Angle α, β, γ (deg.)90.000, 94.090, 90.000
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: 34689.543 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: Escherichia coli (E. coli)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-LKQ / ~{N}-[3-[2-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]-5-methyl-pyrimidin-4-yl]-1~{H}-indol-7-yl]-2-methyl-pyridine-3-carboxamide


Mass: 468.510 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H24N8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 2.45 Å3/Da / Density % sol: 49.76 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 27% (m/v) PEG6000, 0.1 M MES/NaOH pH 6.0 and 5 mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.9999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 1, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9999 Å / Relative weight: 1
ReflectionResolution: 2.04→85 Å / Num. obs: 38500 / % possible obs: 95.8 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.085 / Net I/σ(I): 10.03
Reflection shellResolution: 2.04→2.29 Å / Rmerge(I) obs: 0.443 / Mean I/σ(I) obs: 2.8 / Num. unique obs: 10499

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XSCALEdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.04→39.34 Å / Cor.coef. Fo:Fc: 0.899 / Cor.coef. Fo:Fc free: 0.862 / SU R Cruickshank DPI: 0.233 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.226 / SU Rfree Blow DPI: 0.191 / SU Rfree Cruickshank DPI: 0.195
RfactorNum. reflection% reflectionSelection details
Rfree0.265 1848 4.8 %RANDOM
Rwork0.221 ---
obs0.224 38496 96.3 %-
Displacement parametersBiso max: 113.83 Å2 / Biso mean: 38.2 Å2 / Biso min: 9.68 Å2
Baniso -1Baniso -2Baniso -3
1-2.7174 Å20 Å20.473 Å2
2---8.6674 Å20 Å2
3---5.95 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.04→39.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4624 0 70 211 4905
Biso mean--25.69 34.19 -
Num. residues----570
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1708SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes800HARMONIC5
X-RAY DIFFRACTIONt_it4822HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion587SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5693SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4822HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6511HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion17.73
LS refinement shellResolution: 2.04→2.06 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.282 36 4.68 %
Rwork0.2247 734 -
all0.2274 770 -
obs--80.78 %
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)
13.0626-0.85370.21242.33120.63135.10290.11380.43430.4192-0.4534-0.0166-0.2942-0.55450.23-0.0972-0.12180.0077-0.0087-0.121-0.01470.023624.235-3.642-2.827
23.58480.3425-0.23993.45080.67241.11020.0246-0.23450.44940.2910.01220.1948-0.0973-0.0228-0.0368-0.13550.0269-0.073-0.2234-0.0333-0.00568.0713.19915.524
33.2516-0.29850.52272.4264-1.53045.1680.06790.4463-0.6265-0.4920.07980.2590.5685-0.0441-0.1478-0.1226-0.0325-0.1025-0.1429-0.06690.3788-2.92250.253-2.673
42.57480.17190.4653.0633-0.65231.14060.0006-0.1189-0.30630.30220.0566-0.02090.08880.0382-0.0572-0.1183-0.0058-0.0308-0.2431-0.01350.183913.21943.25515.768
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|867 - A|959 }A867 - 959
2X-RAY DIFFRACTION2{ A|961 - A|1153 }A961 - 1153
3X-RAY DIFFRACTION3{ B|867 - B|959 }B867 - 959
4X-RAY DIFFRACTION4{ B|961 - B|1153 }B961 - 1153

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