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- PDB-4z16: Crystal Structure of the Jak3 Kinase Domain Covalently Bound to N... -

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Basic information

Entry
Database: PDB / ID: 4z16
TitleCrystal Structure of the Jak3 Kinase Domain Covalently Bound to N-(3-(((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)methyl)phenyl)acrylamide
ComponentsTyrosine-protein kinase JAK3
KeywordsTransferase/Transferase Inhibitor / tyrosine kinase / kinase domain / covalent inhibitor complex / 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 / Signaling by ALK / extrinsic component of plasma membrane / 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 / protein phosphatase binding / protein tyrosine kinase activity / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / Potential therapeutics for SARS / adaptive immune response / 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-4LH / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsMcNally, R. / Tan, L. / Gray, N.S. / Eck, M.J.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Development of Selective Covalent Janus Kinase 3 Inhibitors.
Authors: Tan, L. / Akahane, K. / McNally, R. / Reyskens, K.M. / Ficarro, S.B. / Liu, S. / Herter-Sprie, G.S. / Koyama, S. / Pattison, M.J. / Labella, K. / Johannessen, L. / Akbay, E.A. / Wong, K.K. / ...Authors: Tan, L. / Akahane, K. / McNally, R. / Reyskens, K.M. / Ficarro, S.B. / Liu, S. / Herter-Sprie, G.S. / Koyama, S. / Pattison, M.J. / Labella, K. / Johannessen, L. / Akbay, E.A. / Wong, K.K. / Frank, D.A. / Marto, J.A. / Look, T.A. / Arthur, J.S. / Eck, M.J. / Gray, N.S.
History
DepositionMar 26, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 10, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 27, 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 / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Nov 15, 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

Downloads & links

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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)145,8758
Polymers143,8434
Non-polymers2,0324
Water82946
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4692
Polymers35,9611
Non-polymers5081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4692
Polymers35,9611
Non-polymers5081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4692
Polymers35,9611
Non-polymers5081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4692
Polymers35,9611
Non-polymers5081
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.625, 68.207, 93.130
Angle α, β, γ (deg.)92.64, 93.06, 86.20
Int Tables number1
Space group name H-MP1

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Components

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


Mass: 35960.840 Da / Num. of mol.: 4 / Fragment: UNP residues 811-1124
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK3 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Chemical
ChemComp-4LH / N-(3-{[(5-chloro-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]methyl}phenyl)prop-2-enamide


Mass: 508.015 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H30ClN7O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 46 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsQS to PE conflict in UNP entry P52333

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.71 Å3/Da / Density % sol: 54.54 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M Bis-tris pH 6.5, 16% PEG 3350, 0.2 M ammonium sulfate, 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.9→92.91 Å / Num. obs: 30357 / % possible obs: 97 % / Redundancy: 2.2 % / Biso Wilson estimate: 64.79 Å2 / Rsym value: 0.13 / Net I/σ(I): 7.1

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
XDSJanuary 10, 2014data reduction
SCALA3.3.21data scaling
PHASER2.5.6phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YVJ

1yvj


Resolution: 2.9→92.91 Å / Cor.coef. Fo:Fc: 0.8894 / Cor.coef. Fo:Fc free: 0.8563 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.365
RfactorNum. reflection% reflectionSelection details
Rfree0.2401 1495 4.92 %RANDOM
Rwork0.2021 ---
obs0.204 30356 96.98 %-
Displacement parametersBiso mean: 65.05 Å2
Baniso -1Baniso -2Baniso -3
1-8.807 Å2-4.2871 Å24.6577 Å2
2---14.5404 Å217.0635 Å2
3---5.7334 Å2
Refine analyzeLuzzati coordinate error obs: 0.423 Å
Refinement stepCycle: 1 / Resolution: 2.9→92.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8711 0 144 46 8901
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0089229HARMONIC2
X-RAY DIFFRACTIONt_angle_deg112473HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3257SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes202HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1330HARMONIC5
X-RAY DIFFRACTIONt_it9229HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.1
X-RAY DIFFRACTIONt_other_torsion19.2
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1080SEMIHARMONIC5
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_contact10125SEMIHARMONIC4
LS refinement shellResolution: 2.9→3 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2619 124 4.27 %
Rwork0.2244 2777 -
all0.2262 2901 -
obs--96.98 %
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)
12.5456-2.01460.51541.59120.05046.8577-0.0183-0.0644-0.2561-0.17830.0532-0.03880.0020.3613-0.0349-0.3009-0.09810.0565-0.1321-0.1672-0.00150.5965-22.98158.2012
22.3408-0.9924-0.15242.56060.44742.9934-0.0360.07360.1288-0.25070.0972-0.2047-0.40640.0217-0.0612-0.1351-0.06710.0473-0.1451-0.0797-0.0953-12.9249-1.973313.4411
33.5388-0.56771.35726.37732.23254.1316-0.00110.20790.0934-0.1334-0.07180.38560.0755-0.03110.0729-0.3128-0.02840.0240.0221-0.1352-0.185112.040712.0924-37.3507
42.4639-0.55720.7872.168-0.10993.4690.0103-0.0904-0.20490.17690.0987-0.03280.27810.0082-0.109-0.2207-0.0531-0.0057-0.124-0.0623-0.132725.34629.3746-15.9936
54.53592.0127-1.38315.87910.16147.32240.0219-0.04470.2488-0.0195-0.09360.1748-0.14110.35230.0717-0.2954-0.0188-0.0011-0.0468-0.1473-0.1829.4753-1.549240.3619
63.69241.85840.83493.14460.60942.22360.1563-0.1832-0.4040.17820.0226-0.10630.2379-0.0295-0.1789-0.2136-0.0031-0.0578-0.1339-0.094-0.077816.0609-22.574534.7905
72.64810.5612-1.88194.91010.52965.72510.0152-0.20830.008-0.0019-0.1230.35740.0823-0.02610.1077-0.2789-0.0304-0.0235-0.0701-0.1446-0.0859-21.5476-33.4409-6.3364
84.0033-1.1581-3.07680.9805-0.14115.87050.2310.45220.2661-0.2237-0.1479-0.0751-0.4705-0.2528-0.083-0.23940.07360.0196-0.0708-0.0806-0.2184-8.1965-31.6792-27.877
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|814 - A|907 }A814 - 907
2X-RAY DIFFRACTION2{ A|908 - A|1103}A908 - 1103
3X-RAY DIFFRACTION3{ B|814 - B|907 }B814 - 907
4X-RAY DIFFRACTION4{ B|908 - B|1103 }B908 - 1103
5X-RAY DIFFRACTION5{ C|814 - C|907 }C814 - 907
6X-RAY DIFFRACTION6{ C|908 - C|1103 }C908 - 1103
7X-RAY DIFFRACTION7{ D|814 - D|907 }D814 - 907
8X-RAY DIFFRACTION8{ D|908 - D|1103 }D908 - 1103

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