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- PDB-6rse: Structure based optimization of JAK1-ATP binding pocket Inhibitor... -

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Basic information

Entry
Database: PDB / ID: 6rse
TitleStructure based optimization of JAK1-ATP binding pocket Inhibitors in the aminopyrazole class
ComponentsTyrosine-protein kinase JAK1
KeywordsTRANSFERASE / 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 / 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-KHH / Tyrosine-protein kinase JAK1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsBrown, D.G. / Lupardus, P.J.
CitationJournal: To Be Published
Title: Structure based optimization of JAK1-ATP binding pocket Inhibitors in the aminopyrazole class
Authors: Zak, M. / Gibbons, P. / Brown, D.G.
History
DepositionMay 21, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 8, 2020Provider: repository / Type: Initial release

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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)70,4424
Polymers69,4932
Non-polymers9492
Water5,585310
1
A: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2212
Polymers34,7471
Non-polymers4741
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2212
Polymers34,7471
Non-polymers4741
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.890, 88.960, 173.810
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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
Details: Phosphotyrosine / Source: (gene. exp.) Homo sapiens (human) / Gene: JAK1, JAK1A, JAK1B
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: P23458, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-KHH / methyl ~{N}-[4-aminocarbonyl-1-[(3~{R},4~{R})-4-(cyanomethyl)-1-[(4-ethenyl-2-fluoranyl-5-oxidanyl-phenyl)methyl]-3-fluoranyl-piperidin-4-yl]pyrazol-3-yl]carbamate


Mass: 474.461 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24F2N6O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 310 / 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: 2.52 Å3/Da / Density % sol: 51.15 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 5.6 / Details: 0.1M MES. 25-35% PEG6000

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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: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 3, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.8→39.04 Å / Num. obs: 62372 / % possible obs: 99.4 % / Redundancy: 6.5 % / Net I/σ(I): 27.3
Reflection shellResolution: 1.8→1.83 Å / Num. unique obs: 3059 / CC1/2: 0.573

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.22data extraction
xia2data reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→39.04 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.92 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.172 / ESU R Free: 0.162
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.3035 3063 4.9 %RANDOM
Rwork0.2631 ---
obs0.2651 59235 99.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 102.66 Å2 / Biso mean: 32.583 Å2 / Biso min: 14.01 Å2
Baniso -1Baniso -2Baniso -3
1--0.73 Å2-0 Å20 Å2
2--1.37 Å2-0 Å2
3----0.64 Å2
Refinement stepCycle: final / Resolution: 1.8→39.04 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4613 0 68 310 4991
Biso mean--21.73 37.57 -
Num. residues----567
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0134796
X-RAY DIFFRACTIONr_bond_other_d0.0340.0174462
X-RAY DIFFRACTIONr_angle_refined_deg1.9991.6546475
X-RAY DIFFRACTIONr_angle_other_deg2.3121.58210405
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.4495564
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.50122.922243
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.46115880
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2431526
X-RAY DIFFRACTIONr_chiral_restr0.4170.2594
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.025224
X-RAY DIFFRACTIONr_gen_planes_other0.020.02972
X-RAY DIFFRACTIONr_mcbond_it2.0143.3382268
X-RAY DIFFRACTIONr_mcbond_other2.0133.3372267
X-RAY DIFFRACTIONr_mcangle_it3.4154.9912828
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.38 200 -
Rwork0.381 4341 -
all-4541 -
obs--99.65 %

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