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- PDB-3zc6: Crystal structure of JAK3 kinase domain in complex with an indazo... -

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Basic information

Entry
Database: PDB / ID: 3zc6
TitleCrystal structure of JAK3 kinase domain in complex with an indazole substituted pyrrolopyrazine inhibitor
ComponentsTYROSINE-PROTEIN KINASE JAK3
KeywordsTRANSFERASE / SCID / SEVERE COMBINED IMMUNODEFICIENCY / STAT5 / STAT6 / INTERLEUKIN-2 / COMMON-GAMMA CHAIN / ATP SITE KINASE INHIBITOR / CANCER
Function / homology
Function and homology information


negative regulation of dendritic cell cytokine 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 / tyrosine phosphorylation of STAT protein / negative regulation of T-helper 17 cell lineage commitment / Interleukin-9 signaling ...negative regulation of dendritic cell cytokine 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 / tyrosine phosphorylation of STAT protein / negative regulation of 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 / negative regulation of T cell activation / interleukin-2-mediated signaling pathway / regulation of T cell apoptotic process / negative regulation of interleukin-12 production / interleukin-15-mediated signaling pathway / growth hormone receptor binding / negative regulation of thymocyte apoptotic process / Interleukin-15 signaling / regulation of receptor signaling pathway via JAK-STAT / Interleukin-2 signaling / extrinsic component of cytoplasmic side of plasma membrane / extrinsic component of plasma membrane / Interleukin-20 family signaling / Signaling by ALK / negative regulation of interleukin-10 production / enzyme-linked receptor protein signaling pathway / T cell homeostasis / growth hormone receptor signaling pathway via JAK-STAT / cell surface receptor signaling pathway via JAK-STAT / Interleukin receptor SHC signaling / Interleukin-7 signaling / B cell differentiation / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / cytokine-mediated signaling pathway / cytoplasmic side of plasma membrane / RAF/MAP kinase cascade / protein tyrosine kinase activity / protein phosphatase binding / Interleukin-4 and Interleukin-13 signaling / regulation of apoptotic process / adaptive immune response / Potential therapeutics for SARS / cell differentiation / cytoskeleton / endosome / intracellular signal transduction / 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 / : / 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 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 / : / SH2 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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
DI(HYDROXYETHYL)ETHER / Chem-VFC / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.42 Å
AuthorsKuglstatter, A. / Jestel, A. / Nagel, S. / Boettcher, J. / Blaesse, M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2013
Title: Strategic Use of Conformational Bias and Structure Based Design to Identify Potent Jak3 Inhibitors with Improved Selectivity Against the Jak Family and the Kinome.
Authors: Lynch, S.M. / Devicente, J. / Hermann, J.C. / Jaime-Figueroa, S. / Jin, S. / Kuglstatter, A. / Li, H. / Lovey, A. / Menke, J. / Niu, L. / Patel, V. / Roy, D. / Soth, M. / Steiner, S. / ...Authors: Lynch, S.M. / Devicente, J. / Hermann, J.C. / Jaime-Figueroa, S. / Jin, S. / Kuglstatter, A. / Li, H. / Lovey, A. / Menke, J. / Niu, L. / Patel, V. / Roy, D. / Soth, M. / Steiner, S. / Tivitmahaisoon, P. / Vu, M.D. / Yee, C.
History
DepositionNov 16, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 25, 2013Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 650 HELIX DETERMINATION METHOD: AUTHOR PROVIDED.
Remark 700 SHEET DETERMINATION METHOD: AUTHOR PROVIDED.

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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)134,42216
Polymers131,8944
Non-polymers2,52812
Water6,918384
1
A: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6326
Polymers32,9741
Non-polymers6595
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7204
Polymers32,9741
Non-polymers7473
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6143
Polymers32,9741
Non-polymers6412
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: TYROSINE-PROTEIN KINASE JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,4553
Polymers32,9741
Non-polymers4822
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)57.170, 117.725, 105.831
Angle α, β, γ (deg.)90.00, 97.66, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 32973.516 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN, RESIDUES 813-1100 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P52333, non-specific protein-tyrosine kinase, EC: 2.7.1.112

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Non-polymers , 5 types, 396 molecules

#2: Chemical
ChemComp-VFC / N-[(2R)-1-(3-cyanoazetidin-1-yl)-1-oxidanylidene-propan-2-yl]-2-(6-fluoranyl-1-methyl-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide


Mass: 446.437 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H19FN8O2
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 384 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.73 Å3/Da / Density % sol: 55.02 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 18, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.42→104.89 Å / Num. obs: 52977 / % possible obs: 99.8 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.08
Reflection shellResolution: 2.42→2.51 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.42 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
XDSdata reduction
XSCALEdata scaling
REFMACRIGID BODYphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.42→104.89 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.909 / SU B: 17.09 / SU ML: 0.191 / Cross valid method: THROUGHOUT / ESU R: 0.391 / ESU R Free: 0.266 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED SIDE CHAINS HAVE OCCUPANCY 0.00
RfactorNum. reflection% reflectionSelection details
Rfree0.25385 1129 2.1 %RANDOM
Rwork0.1913 ---
obs0.1926 51759 99.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 48.801 Å2
Baniso -1Baniso -2Baniso -3
1--0.91 Å20 Å20.41 Å2
2---1.56 Å20 Å2
3---2.58 Å2
Refinement stepCycle: LAST / Resolution: 2.42→104.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8893 0 176 384 9453
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0229392
X-RAY DIFFRACTIONr_bond_other_d0.0020.026662
X-RAY DIFFRACTIONr_angle_refined_deg1.2062.00212748
X-RAY DIFFRACTIONr_angle_other_deg1.764316020
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.55951137
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.86122.542417
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.203151563
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.0181587
X-RAY DIFFRACTIONr_chiral_restr0.0670.21341
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.02110398
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022013
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.56625652
X-RAY DIFFRACTIONr_mcbond_other0.25522253
X-RAY DIFFRACTIONr_mcangle_it2.68939082
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.29443740
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it6.07663658
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
LS refinement shellResolution: 2.42→2.483 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.316 98 -
Rwork0.228 3831 -
obs--99.97 %
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)
13.35651.87160.10896.75850.39561.6725-0.1194-0.183-0.33180.11130.0904-0.75460.17510.29490.02910.03660.0369-0.00070.07020.0130.093318.2-1.83252.659
22.3258-0.02630.35823.9316-0.44582.8209-0.00950.36240.1968-0.48160.0075-0.0543-0.05930.05870.0020.06840.00940.01180.08920.04310.02264.68113.59337.695
31.9243-1.14270.37597.16450.76811.6941-0.06120.08370.187-0.16180.1483-0.7826-0.1550.2376-0.08720.0206-0.01380.01720.0576-0.01250.0883-10.43436.62951.813
42.38310.051-0.53314.1534-0.13352.57650.0872-0.5064-0.10390.5928-0.055-0.12250.12970.0494-0.03230.1058-0.0381-0.02230.1220.02660.0299-23.96720.71666.702
52.8088-0.6874-0.1525.83530.40951.941-0.14770.03140.4027-0.10480.1728-0.6343-0.19730.2038-0.0250.0557-0.0086-0.01920.0794-0.03010.149-3.5231.161-1.304
62.22160.4495-0.41193.4428-0.32562.8048-0.0125-0.57320.01010.5184-0.0101-0.08420.09630.09220.02250.1101-0.0002-0.03120.2085-0.01780.0378-16.671-13.50614.087
73.22611.11871.18526.78050.82111.2475-0.0463-0.0808-0.57010.22690.2197-0.63960.16440.2169-0.17330.08060.02870.00940.10620.01150.137925.25-37.0171.12
82.8525-0.11230.53953.9065-0.15943.3138-0.05240.45360.064-0.4330.020.0304-0.08440.01070.03230.05710.0056-0.01040.1265-0.00710.008111.271-22.214-13.745
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 904
2X-RAY DIFFRACTION2A905 - 2000
3X-RAY DIFFRACTION3B1 - 904
4X-RAY DIFFRACTION4B905 - 2000
5X-RAY DIFFRACTION5C1 - 904
6X-RAY DIFFRACTION6C905 - 2000
7X-RAY DIFFRACTION7D1 - 904
8X-RAY DIFFRACTION8D905 - 2000

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