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- PDB-7uyv: Crystal structure of JAK3 kinase domain in complex with compound 25 -

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Basic information

Entry
Database: PDB / ID: 7uyv
TitleCrystal structure of JAK3 kinase domain in complex with compound 25
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / non-receptor tyrosine-protein kinase JAK3 / 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 / 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-OV5 / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.15 Å
AuthorsToms, A.V. / Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. ...Toms, A.V. / Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Shelley, M. / Wester, R.T. / Westlin, W. / Mc Elwee, J.J. / Miao, W. / Edmondson, S.D. / Massee, C.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2022
Title: Potent and selective TYK2-JH1 inhibitors highly efficacious in rodent model of psoriasis.
Authors: Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Toms, A.V. / Shelley, M. / Wester, ...Authors: Leit, S. / Greenwood, J.R. / Mondal, S. / Carriero, S. / Dahlgren, M. / Harriman, G.C. / Kennedy-Smith, J.J. / Kapeller, R. / Lawson, J.P. / Romero, D.L. / Toms, A.V. / Shelley, M. / Wester, R.T. / Westlin, W. / McElwee, J.J. / Miao, W. / Edmondson, S.D. / Masse, C.E.
History
DepositionMay 7, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2022Provider: 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
C: Tyrosine-protein kinase JAK3
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)134,8349
Polymers133,1034
Non-polymers1,7315
Water7,891438
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7002
Polymers33,2761
Non-polymers4241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7002
Polymers33,2761
Non-polymers4241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7002
Polymers33,2761
Non-polymers4241
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,7353
Polymers33,2761
Non-polymers4592
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.074, 114.166, 106.086
Angle α, β, γ (deg.)90.000, 97.540, 90.000
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: 33275.871 Da / Num. of mol.: 4 / Fragment: KINASE DOMAIN
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-OV5 / 6-{[(2M)-2-(2-chloro-6-fluorophenyl)-5-oxo-5H-pyrrolo[3,4-b]pyridin-4-yl]amino}-N-ethylpyridine-3-carboxamide


Mass: 423.828 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H15ClFN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 438 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.7 Å3/Da / Density % sol: 53.3 %
Crystal growTemperature: 298 K / Method: vapor diffusion
Details: Crystals of human JAK3 in complex with the ligand were prepared according to established protocols

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→105.17 Å / Num. obs: 70329 / % possible obs: 96 % / Redundancy: 2.8 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 14.04
Reflection shellResolution: 2.15→2.4 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.434 / Mean I/σ(I) obs: 2.76 / Num. unique obs: 19754 / Rrim(I) all: 0.539 / % possible all: 96.3

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMAC5.2.0005refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.15→105.17 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.911 / SU B: 17.207 / SU ML: 0.222 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.268 / ESU R Free: 0.214 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2629 1558 2.2 %RANDOM
Rwork0.2206 ---
obs0.2215 68763 96.04 %-
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 max: 123.93 Å2 / Biso mean: 39.447 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--1.18 Å20 Å20.13 Å2
2---2.17 Å20 Å2
3---3.39 Å2
Refinement stepCycle: final / Resolution: 2.15→105.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8984 0 116 438 9538
Biso mean--19.53 18.18 -
Num. residues----1115
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0229248
X-RAY DIFFRACTIONr_bond_other_d0.0020.028387
X-RAY DIFFRACTIONr_angle_refined_deg1.0851.99812569
X-RAY DIFFRACTIONr_angle_other_deg1.247319384
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.1551129
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.96622.822404
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.455151507
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5571576
X-RAY DIFFRACTIONr_chiral_restr0.0610.21339
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0210296
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021966
X-RAY DIFFRACTIONr_nbd_refined0.1550.21557
X-RAY DIFFRACTIONr_nbd_other0.1420.27796
X-RAY DIFFRACTIONr_nbtor_refined0.1560.24391
X-RAY DIFFRACTIONr_nbtor_other0.0660.24771
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0810.2397
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0640.215
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1090.2121
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0680.217
LS refinement shellResolution: 2.15→2.206 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.349 120 -
Rwork0.313 5082 -
all-5202 -
obs--96.57 %
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)
13.16470.65350.72119.29990.26871.4403-0.0277-0.0655-0.34780.25710.0762-1.03470.02010.3185-0.0484-0.1989-0.0053-0.0565-0.1564-0.0043-0.079919.477-37.05457.398
21.31980.55440.51774.1897-0.25073.4075-0.03070.32550.1011-0.4922-0.0156-0.3357-0.03420.16440.0464-0.17070.04630.0254-0.1222-0.0033-0.18426.136-24.75439.482
32.6453-1.8674-0.28478.9214-0.40621.9213-0.06190.19320.2544-0.22510.0003-0.9387-0.04420.41370.0615-0.20390.00080.0425-0.1349-0.0111-0.1466-8.8320.98747.588
41.61840.4816-0.21113.6344-0.34832.85120.0501-0.3116-0.11440.4645-0.0889-0.21430.07180.09640.0387-0.1721-0.0453-0.0209-0.11460.0109-0.187-22.277-11.06466.04
54.8145-1.3202-0.0647.76491.61112.4196-0.0841-0.03980.4922-0.1410.2198-0.7715-0.35810.1837-0.1357-0.04930.00520.0234-0.04580.0023-0.1312-16.79240.349104.805
62.15960.5578-1.32413.6241-1.11855.1367-0.02-0.1686-0.12970.2105-0.057-0.132-0.059-0.09520.077-0.149-0.0215-0.0197-0.0439-0.0001-0.1537-29.15123.756119.565
74.45640.94160.78647.33432.03242.5905-0.05090.0617-0.39840.17860.3127-1.02060.36380.4417-0.2619-0.07660.01-0.06250.0024-0.02170.004311.9581.436105.247
82.9487-0.09061.585.22120.7894.34710.04150.35560.0418-0.81830.0929-0.3977-0.3140.1015-0.13440.0013-0.00360.0835-0.04880.0203-0.217-1.317.98190.591
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A814 - 904
2X-RAY DIFFRACTION2A905 - 1100
3X-RAY DIFFRACTION3B814 - 904
4X-RAY DIFFRACTION4B905 - 1100
5X-RAY DIFFRACTION5C812 - 904
6X-RAY DIFFRACTION6C905 - 1100
7X-RAY DIFFRACTION7D814 - 904
8X-RAY DIFFRACTION8D905 - 1100

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