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- PDB-7apf: Crystal structure of JAK3 in complex with FM601 (compound 10a) -

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Basic information

Entry
Database: PDB / ID: 7apf
TitleCrystal structure of JAK3 in complex with FM601 (compound 10a)
ComponentsTyrosine-protein kinase JAK3
KeywordsTRANSFERASE / kinase / JAK3 / inhibitor / covalent inhibitor / Structural Genomics / Structural Genomics Consortium / SGC
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 / 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
1-phenylurea / Chem-RQZ / Tyrosine-protein kinase JAK3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 Å
AuthorsChaikuad, A. / Forster, M. / Gehringer, M. / Laufer, S. / Knapp, S. / Structural Genomics Consortium (SGC)
CitationJournal: Int J Mol Sci / Year: 2020
Title: Discovery of a Novel Class of Covalent Dual Inhibitors Targeting the Protein Kinases BMX and BTK.
Authors: Forster, M. / Liang, X.J. / Schroder, M. / Gerstenecker, S. / Chaikuad, A. / Knapp, S. / Laufer, S. / Gehringer, M.
History
DepositionOct 16, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 2, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)68,22014
Polymers66,8352
Non-polymers1,38612
Water5,405300
1
A: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1728
Polymers33,4171
Non-polymers7557
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase JAK3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,0486
Polymers33,4171
Non-polymers6315
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.667, 62.498, 67.869
Angle α, β, γ (deg.)90.000, 101.320, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: PRO / Beg label comp-ID: PRO / End auth comp-ID: ARG / End label comp-ID: ARG / Refine code: 0 / Auth seq-ID: 814 - 1103 / Label seq-ID: 5 - 294

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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


Mass: 33417.281 Da / Num. of mol.: 2
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-RQZ / 3-[3-(propanoylamino)phenyl]-1~{H}-pyrrolo[2,3-b]pyridine-5-carboxamide


Mass: 308.335 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H16N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PHU / 1-phenylurea / Phenylurea


Mass: 136.151 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H8N2O
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 300 / 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: 1.98 Å3/Da / Density % sol: 37.91 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 5.5 / Details: 25% PEG 3350, 0.1-0.2 M MgCl2, 0.1 M MES, pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.99986 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Apr 18, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99986 Å / Relative weight: 1
ReflectionResolution: 1.95→45.56 Å / Num. obs: 37245 / % possible obs: 97.6 % / Redundancy: 6 % / CC1/2: 0.994 / Rmerge(I) obs: 0.108 / Rpim(I) all: 0.052 / Rrim(I) all: 0.129 / Net I/σ(I): 8.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.95-2.026.10.7212.436300.8230.350.87297.7
7.55-45.565.90.0756990.9950.0340.08299.5

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Processing

Software
NameVersionClassification
Aimless0.7.1data scaling
REFMAC5.8.0222refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5lwm
Resolution: 1.95→45.56 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.922 / SU B: 10.157 / SU ML: 0.15 / SU R Cruickshank DPI: 0.2364 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.236 / ESU R Free: 0.193 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2549 1868 5 %RANDOM
Rwork0.2035 ---
obs0.2062 35361 97.27 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 106.78 Å2 / Biso mean: 33.379 Å2 / Biso min: 13.63 Å2
Baniso -1Baniso -2Baniso -3
1--0.08 Å20 Å2-0.1 Å2
2--1.27 Å20 Å2
3----1.07 Å2
Refinement stepCycle: final / Resolution: 1.95→45.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4588 0 144 300 5032
Biso mean--27.18 35.92 -
Num. residues----575
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0144894
X-RAY DIFFRACTIONr_bond_other_d0.0010.0174327
X-RAY DIFFRACTIONr_angle_refined_deg1.2991.6476607
X-RAY DIFFRACTIONr_angle_other_deg0.9331.65610158
X-RAY DIFFRACTIONr_dihedral_angle_1_deg19.8365.493609
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.11920.337267
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.2115798
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.0121548
X-RAY DIFFRACTIONr_chiral_restr0.0770.2571
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026559
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02933
Refine LS restraints NCS

Ens-ID: 1 / Number: 9214 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.11 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 1.95→2.001 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 158 -
Rwork0.265 2586 -
all-2744 -
obs--97.41 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
12.89090.5011-0.28310.82730.02140.14030.06860.2870.00740.12780.00920.07210.0181-0.0275-0.07780.0828-0.0156-0.03920.04920.00330.0926-79.1758.4252-40.4539
21.2733-0.2257-0.37630.3975-0.15050.57780.00340.09120.0179-0.02410.011-0.00970.0463-0.0271-0.01440.0824-0.0028-0.06880.00950.00260.0605-53.35819.2767-44.2462
32.09030.0382-0.64550.22690.25091.02810.0507-0.25090.1417-0.0401-0.00390.02270.0292-0.0032-0.04680.0827-0.0113-0.06010.0462-0.02180.0654-44.58439.5692-9.0601
41.6619-0.0916-0.98221.08890.11141.3411-0.1028-0.47870.0597-0.11830.1084-0.06990.04850.5294-0.00550.0720.0255-0.05170.234-0.02510.0703-22.40188.1562-11.3367
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A814 - 908
2X-RAY DIFFRACTION2A909 - 1103
3X-RAY DIFFRACTION3B814 - 990
4X-RAY DIFFRACTION4B991 - 1103

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