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- PDB-5w86: CRYSTAL STRUCTURE OF JAK3 KINASE DOMAIN WITH A 4,6-DIAMINONICOTIN... -

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Basic information

Entry
Database: PDB / ID: 5w86
TitleCRYSTAL STRUCTURE OF JAK3 KINASE DOMAIN WITH A 4,6-DIAMINONICOTINAMIDE INHIBITOR (COMPOUND NUMBER 7)
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / SERINE/THREONINE PROTEIN KINASE / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine production / negative regulation of FasL production / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / negative regulation of T cell activation / Interleukin-9 signaling / Interleukin-21 signaling ...negative regulation of dendritic cell cytokine production / negative regulation of FasL production / response to interleukin-9 / response to interleukin-2 / response to interleukin-15 / response to interleukin-4 / negative regulation of T-helper 1 cell differentiation / negative regulation of T cell activation / Interleukin-9 signaling / Interleukin-21 signaling / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / tyrosine phosphorylation of STAT protein / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / Interleukin-2 signaling / regulation of receptor signaling pathway via JAK-STAT / growth hormone receptor binding / extrinsic component of plasma membrane / Signaling by ALK / negative regulation of interleukin-10 production / Interleukin-20 family signaling / enzyme-linked receptor protein signaling pathway / T cell homeostasis / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / extrinsic component of cytoplasmic side of plasma membrane / Interleukin-7 signaling / B cell differentiation / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytokine-mediated signaling pathway / peptidyl-tyrosine phosphorylation / RAF/MAP kinase cascade / regulation of apoptotic process / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / adaptive immune response / Potential therapeutics for SARS / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / protein phosphorylation / innate immune response / ATP binding / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak3 / 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 domain / FERM domain profile. ...Tyrosine-protein kinase, non-receptor Jak3 / 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 domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / 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. / PH-like domain superfamily / 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-9YV / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.61 Å
AuthorsSack, J.S.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors.
Authors: Bhide, R.S. / Keon, A. / Weigelt, C. / Sack, J.S. / Schmidt, R.J. / Lin, S. / Xiao, H.Y. / Spergel, S.H. / Kempson, J. / Pitts, W.J. / Carman, J. / Poss, M.A.
History
DepositionJun 21, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK3
B: Tyrosine-protein kinase JAK3
C: Tyrosine-protein kinase JAK3
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)133,2688
Polymers131,4344
Non-polymers1,8344
Water2,792155
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3172
Polymers32,8581
Non-polymers4591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3172
Polymers32,8581
Non-polymers4591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3172
Polymers32,8581
Non-polymers4591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3172
Polymers32,8581
Non-polymers4591
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.983, 112.297, 97.119
Angle α, β, γ (deg.)90.00, 90.06, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Tyrosine-protein kinase JAK3 / Janus kinase 3 / JAK-3 / Leukocyte janus kinase / L-JAK


Mass: 32858.430 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN (UNP RESIDUES 810-1100) / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-9YV / 4-(benzylamino)-6-({4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)pyridine-3-carboxamide


Mass: 458.555 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H30N6O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 155 / 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: 2.45 Å3/Da / Density % sol: 49.8 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.0073 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 20, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0073 Å / Relative weight: 1
ReflectionResolution: 2.61→56.98 Å / Num. obs: 37235 / % possible obs: 98 % / Observed criterion σ(I): 0 / Redundancy: 2.8 % / Biso Wilson estimate: 43.61 Å2 / Rmerge(I) obs: 0.132 / Net I/σ(I): 8.5
Reflection shellResolution: 2.61→2.72 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.378 / % possible all: 99.3

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.61→56.98 Å / Cor.coef. Fo:Fc: 0.892 / Cor.coef. Fo:Fc free: 0.841 / SU R Cruickshank DPI: 1.776 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 1.153 / SU Rfree Blow DPI: 0.331 / SU Rfree Cruickshank DPI: 0.342
RfactorNum. reflection% reflectionSelection details
Rfree0.264 1824 5 %RANDOM
Rwork0.209 ---
obs0.211 36498 98 %-
Displacement parametersBiso mean: 30.74 Å2
Baniso -1Baniso -2Baniso -3
1-6.1277 Å20 Å23.0322 Å2
2--7.6544 Å20 Å2
3----13.7821 Å2
Refine analyzeLuzzati coordinate error obs: 0.38 Å
Refinement stepCycle: LAST / Resolution: 2.61→56.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8622 0 136 155 8913
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018951HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1112115HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3068SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes181HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1385HARMONIC5
X-RAY DIFFRACTIONt_it8951HARMONIC20
X-RAY DIFFRACTIONt_nbd15SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.88
X-RAY DIFFRACTIONt_other_torsion18.4
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1072SEMIHARMONIC5
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_contact10058SEMIHARMONIC4
LS refinement shellResolution: 2.61→2.69 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.3135 150 5 %
Rwork0.2207 2853 -
all0.2255 3003 -
obs--99.02 %

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