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- PDB-4v0g: JAK3 in complex with a covalent EGFR inhibitor -

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Basic information

Entry
Database: PDB / ID: 4v0g
TitleJAK3 in complex with a covalent EGFR inhibitor
Components(TYROSINE-PROTEIN KINASE JAK3) x 2
KeywordsTRANSFERASE / EGFR MUTANT / T790M
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 / Interleukin-20 family signaling / negative regulation of interleukin-10 production / 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 / intracellular signal transduction / endosome / 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-G9B / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsDebreczeni, J.E. / Hennessy, E.J. / Chuaquini, C. / Ashton, S. / Coclough, N. / Cross, D.A.E. / Eberlein, C. / Gingipalli, L. / Klinowska, T.C.M. / Orme, J.P. ...Debreczeni, J.E. / Hennessy, E.J. / Chuaquini, C. / Ashton, S. / Coclough, N. / Cross, D.A.E. / Eberlein, C. / Gingipalli, L. / Klinowska, T.C.M. / Orme, J.P. / Sha, L. / Wu, X.
CitationJournal: To be Published
Title: Utilisation of Structure Based Design to Identify Novel, Irreversible Inhibitors of the Epidermal Growth Factor Receptor (Egfr) Harboring the Gatekeeper T790M Mutation
Authors: Hennessy, E.J. / Chuaquini, C. / Ashton, S. / Coclough, N. / Cross, D.A.E. / Debreczeni, J.E. / Eberlein, C. / Gingipalli, L. / Klinowska, T.C.M. / Orme, J.P. / Sha, L. / Wu, X.
History
DepositionSep 16, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 13, 2016Provider: 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 JAK3
B: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,7154
Polymers64,6722
Non-polymers1,0432
Water21612
1
A: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8662
Polymers32,3441
Non-polymers5221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8492
Polymers32,3281
Non-polymers5221
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.140, 99.032, 111.373
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A1 - 907
2114B1 - 907
1124A908 - 2000
2124B908 - 2000

NCS ensembles :
ID
1
2

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Components

#1: Protein TYROSINE-PROTEIN KINASE JAK3 / JANUS KINASE 3 / JAK-3 / LEUKOCYTE JANUS KINASE / L-JAK / JANUS KINASE 3


Mass: 32343.893 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP RESIDUES 816-1098
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#2: Protein TYROSINE-PROTEIN KINASE JAK3 / JANUS KINASE 3 / JAK-3 / LEUKOCYTE JANUS KINASE / L-JAK / JANUS KINASE 3


Mass: 32327.830 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP RESIDUES 816-1098
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: P52333, non-specific protein-tyrosine kinase
#3: Chemical ChemComp-G9B / N-[3-(2-{3-amino-6-[1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]pyrazin-2-yl}-1H-benzimidazol-1-yl)phenyl]propanamide


Mass: 521.616 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H31N9O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 2.44 Å3/Da / Density % sol: 49.51 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→73.92 Å / Num. obs: 13200 / % possible obs: 99.7 % / Observed criterion σ(I): 1.5 / Redundancy: 4 % / Rmerge(I) obs: 0.14 / Net I/σ(I): 4.8
Reflection shellResolution: 3→3.24 Å / Redundancy: 4 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 1.7 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→73.92 Å / Cor.coef. Fo:Fc: 0.901 / Cor.coef. Fo:Fc free: 0.869 / SU B: 23.402 / SU ML: 0.44 / Cross valid method: THROUGHOUT / ESU R Free: 0.523 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.29465 593 4.5 %RANDOM
Rwork0.2516 ---
obs0.25359 12552 99.62 %-
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: 32.73 Å2
Baniso -1Baniso -2Baniso -3
1--4.81 Å20 Å20 Å2
2--6.66 Å20 Å2
3----1.85 Å2
Refinement stepCycle: LAST / Resolution: 3→73.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4361 0 78 12 4451
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0214343
X-RAY DIFFRACTIONr_bond_other_d0.0010.023934
X-RAY DIFFRACTIONr_angle_refined_deg0.9892.0045900
X-RAY DIFFRACTIONr_angle_other_deg0.75639039
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4575538
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.64922.701174
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.39415676
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2511531
X-RAY DIFFRACTIONr_chiral_restr0.0530.2636
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.024826
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02917
X-RAY DIFFRACTIONr_nbd_refined0.2080.2916
X-RAY DIFFRACTIONr_nbd_other0.1680.23884
X-RAY DIFFRACTIONr_nbtor_refined0.1780.22099
X-RAY DIFFRACTIONr_nbtor_other0.0810.22359
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1310.288
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0940.216
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1540.252
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1220.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3423469
X-RAY DIFFRACTIONr_mcbond_other0.18621091
X-RAY DIFFRACTIONr_mcangle_it1.63334316
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.19841947
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.25761584
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
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Refine-ID: X-RAY DIFFRACTION

Ens-IDNumberTypeRms dev position (Å)Weight position
11205medium positional0.260.5
22651medium positional0.30.5
11205medium thermal0.252
22651medium thermal0.262
LS refinement shellResolution: 3→3.078 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.356 42 -
Rwork0.271 886 -
obs--97.79 %

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