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- PDB-4gl9: Crystal structure of inhibitory protein SOCS3 in complex with JAK... -

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Basic information

Entry
Database: PDB / ID: 4gl9
TitleCrystal structure of inhibitory protein SOCS3 in complex with JAK2 kinase domain and fragment of GP130 intracellular domain
Components
  • Interleukin-6 receptor subunit beta
  • Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
  • Tyrosine-protein kinase
Keywordstransferase/transferase inhibitor / kinase inhibitor receptor cytokine signalling / phosphorylation / transferase-transferase inhibitor complex
Function / homology
Function and homology information


response to granulocyte macrophage colony-stimulating factor / IFNG signaling activates MAPKs / positive regulation of cell activation / defense response to symbiont / Regulation of IFNG signaling / PTK6 Activates STAT3 / Growth hormone receptor signaling / Signaling by Erythropoietin / Interleukin-4 and Interleukin-13 signaling / Prolactin receptor signaling ...response to granulocyte macrophage colony-stimulating factor / IFNG signaling activates MAPKs / positive regulation of cell activation / defense response to symbiont / Regulation of IFNG signaling / PTK6 Activates STAT3 / Growth hormone receptor signaling / Signaling by Erythropoietin / Interleukin-4 and Interleukin-13 signaling / Prolactin receptor signaling / oncostatin-M receptor activity / Interleukin-20 family signaling / Interferon gamma signaling / Interleukin-12 signaling / Signaling by CSF3 (G-CSF) / IL-6-type cytokine receptor ligand interactions / Erythropoietin activates RAS / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / Interleukin-23 signaling / Interleukin-27 signaling / leukemia inhibitory factor receptor activity / interleukin-6 receptor activity / interleukin-6 binding / Interleukin-6 signaling / Interleukin-35 Signalling / Interferon alpha/beta signaling / oncostatin-M receptor complex / Inactivation of CSF3 (G-CSF) signaling / Signaling by SCF-KIT / ciliary neurotrophic factor receptor binding / ciliary neurotrophic factor receptor complex / Cyclin D associated events in G1 / RAF activation / interleukin-6 receptor complex / interleukin-27-mediated signaling pathway / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Interleukin receptor SHC signaling / RAF/MAP kinase cascade / interleukin-6 receptor binding / interleukin-11-mediated signaling pathway / cellular response to interleukin-17 / regulation of Notch signaling pathway / Factors involved in megakaryocyte development and platelet production / branching involved in labyrinthine layer morphogenesis / nuclear receptor-mediated mineralocorticoid signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / symbiont-induced defense-related programmed cell death / mammary gland epithelium development / regulation of postsynapse to nucleus signaling pathway / Interleukin-3, Interleukin-5 and GM-CSF signaling / positive regulation of growth hormone receptor signaling pathway / interleukin-12 receptor complex / Neddylation / placenta blood vessel development / interleukin-23 receptor complex / granulocyte macrophage colony-stimulating factor receptor complex / granulocyte-macrophage colony-stimulating factor signaling pathway / positive regulation of astrocyte differentiation / thrombopoietin-mediated signaling pathway / collagen-activated signaling pathway / interleukin-12 receptor binding / histone H3Y41 kinase activity / interleukin-5-mediated signaling pathway / interleukin-23-mediated signaling pathway / activation of Janus kinase activity / response to interleukin-12 / intestinal epithelial cell development / negative regulation of receptor signaling pathway via JAK-STAT / positive regulation of T-helper 17 type immune response / interleukin-12-mediated signaling pathway / myeloid cell differentiation / type 1 angiotensin receptor binding / positive regulation of NK T cell proliferation / post-embryonic hemopoiesis / erythropoietin-mediated signaling pathway / positive regulation of MHC class II biosynthetic process / acetylcholine receptor binding / positive regulation of natural killer cell proliferation / positive regulation of platelet activation / growth hormone receptor binding / cellular response to interleukin-3 / interleukin-3-mediated signaling pathway / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of platelet aggregation / protein tyrosine kinase inhibitor activity / cell surface receptor signaling pathway via STAT / positive regulation of epithelial cell apoptotic process / positive regulation of cell-substrate adhesion / extrinsic component of cytoplasmic side of plasma membrane / miRNA binding / axon regeneration / response to hydroperoxide / growth hormone receptor signaling pathway / negative regulation of cardiac muscle cell apoptotic process / positive regulation of tyrosine phosphorylation of STAT protein / intrinsic apoptotic signaling pathway in response to oxidative stress / negative regulation of cell-cell adhesion / peptide hormone receptor binding / glycogen metabolic process
Similarity search - Function
Suppressor of cytokine signalling 3 / SOCS3, SH2 domain / suppressors of cytokine signalling / SOCS box-like domain superfamily / SOCS box domain / SOCS box domain profile. / SOCS_box / : / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding ...Suppressor of cytokine signalling 3 / SOCS3, SH2 domain / suppressors of cytokine signalling / SOCS box-like domain superfamily / SOCS box domain / SOCS box domain profile. / SOCS_box / : / Type I cytokine receptor, cytokine-binding domain / Interleukin-6 receptor alpha chain, binding / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / 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 / SH2 domain / SHC Adaptor Protein / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Fibronectin type III domain / Fibronectin type 3 domain / SH2 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Src homology 2 (SH2) domain profile. / 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. / Immunoglobulin-like fold / 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-IZA / PHOSPHATE ION / Tyrosine-protein kinase JAK2 / Suppressor of cytokine signaling 3 / Interleukin-6 receptor subunit beta / Tyrosine-protein kinase JAK2
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.9 Å
AuthorsKershaw, N.J. / Murphy, J.M. / Laktyushin, A. / Nicola, N.A. / Babon, J.J.
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2013
Title: SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition.
Authors: Kershaw, N.J. / Murphy, J.M. / Liau, N.P. / Varghese, L.N. / Laktyushin, A. / Whitlock, E.L. / Lucet, I.S. / Nicola, N.A. / Babon, J.J.
History
DepositionAug 14, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 17, 2013Group: Database references
Revision 1.2Mar 4, 2015Group: Structure summary
Revision 1.3Aug 9, 2017Group: Data collection / Refinement description / Source and taxonomy
Category: diffrn_detector / entity_src_gen / software / Item: _diffrn_detector.detector
Revision 1.4Jun 13, 2018Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: entity / entity_name_com ...entity / entity_name_com / entity_src_gen / pdbx_entity_src_syn / pdbx_struct_mod_residue / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _entity.pdbx_description / _entity_name_com.name ..._entity.pdbx_description / _entity_name_com.name / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_beg_seq_num / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_seq_type / _pdbx_entity_src_syn.organism_common_name / _pdbx_entity_src_syn.pdbx_beg_seq_num / _pdbx_entity_src_syn.pdbx_end_seq_num / _pdbx_struct_mod_residue.details / _struct_ref.db_code / _struct_ref.db_name / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq.seq_align_beg / _struct_ref_seq.seq_align_end
Revision 1.5Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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 / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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
B: Tyrosine-protein kinase
I: Interleukin-6 receptor subunit beta
C: Tyrosine-protein kinase
K: Interleukin-6 receptor subunit beta
J: Interleukin-6 receptor subunit beta
E: Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
L: Interleukin-6 receptor subunit beta
D: Tyrosine-protein kinase
F: Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
G: Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
H: Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)210,76817
Polymers209,43612
Non-polymers1,3325
Water00
1
A: Tyrosine-protein kinase
K: Interleukin-6 receptor subunit beta
E: Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,6684
Polymers52,3593
Non-polymers3091
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4350 Å2
ΔGint-24 kcal/mol
Surface area18660 Å2
MethodPISA
2
B: Tyrosine-protein kinase
L: Interleukin-6 receptor subunit beta
H: Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7635
Polymers52,3593
Non-polymers4042
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4280 Å2
ΔGint-24 kcal/mol
Surface area18680 Å2
MethodPISA
3
I: Interleukin-6 receptor subunit beta
C: Tyrosine-protein kinase
G: Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,6684
Polymers52,3593
Non-polymers3091
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4540 Å2
ΔGint-27 kcal/mol
Surface area18580 Å2
MethodPISA
4
J: Interleukin-6 receptor subunit beta
D: Tyrosine-protein kinase
F: Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,6684
Polymers52,3593
Non-polymers3091
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4370 Å2
ΔGint-22 kcal/mol
Surface area18790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)139.262, 139.262, 316.742
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number170
Space group name H-MP65

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Components

#1: Protein
Tyrosine-protein kinase


Mass: 35111.883 Da / Num. of mol.: 4 / Fragment: Kinase domain (unp residues 836-1132)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Jak2, mCG_9104 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: G5E852, UniProt: Q62120*PLUS, non-specific protein-tyrosine kinase
#2: Protein/peptide
Interleukin-6 receptor subunit beta / IL-6RB / Interleukin-6 signal transducer / Membrane glycoprotein 130 / gp130 / Oncostatin-M ...IL-6RB / Interleukin-6 signal transducer / Membrane glycoprotein 130 / gp130 / Oncostatin-M receptor subunit alpha


Mass: 1605.573 Da / Num. of mol.: 4 / Fragment: unp residues 750-764 / Source method: obtained synthetically / Source: (synth.) Mus musculus (house mouse) / References: UniProt: Q00560
#3: Protein
Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3,Suppressor of cytokine signaling 3 / SOCS-3 / Cytokine-inducible SH2 protein 3 / CIS-3 / Protein EF-10


Mass: 15641.506 Da / Num. of mol.: 4
Fragment: chimeric fusion of Intracellular domain (unp residues 22-128 and 163-185)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Socs3, Cis3, Cish3 / Production host: Escherichia coli (E. coli) / References: UniProt: O35718
#4: Chemical
ChemComp-IZA / 2-TERT-BUTYL-9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLINE-7-ONE / 2-(1,1-DIMETHYLETHYL)9-FLUORO-3,6-DIHYDRO-7H-BENZ[H]-IMIDAZ[4,5-F]ISOQUINOLIN-7-ONE


Mass: 309.338 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H16FN3O
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
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: 4.23 Å3/Da / Density % sol: 70.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.2
Details: 0.33M di-potassium hydrogen phosphate, 1.67M sodium dihydrogen phosphate, 0.1M phosphate-citrate, pH 4.2, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.95371 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Apr 2, 2011
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.95371 Å / Relative weight: 1
ReflectionResolution: 3.9→45.584 Å / Num. obs: 31617 / % possible obs: 99.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
PHENIX(phenix.refine: 1.8_1069)refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.9→45.58 Å / σ(F): 1.99 / Phase error: 36.69 / Stereochemistry target values: TWIN_LSQ_F
RfactorNum. reflection% reflection
Rfree0.2808 1588 5.02 %
Rwork0.2495 --
obs0.254 31617 99.98 %
all-20680 -
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3.9→45.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13585 0 97 0 13682
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00213980
X-RAY DIFFRACTIONf_angle_d0.60818889
X-RAY DIFFRACTIONf_dihedral_angle_d12.8535253
X-RAY DIFFRACTIONf_chiral_restr0.0382027
X-RAY DIFFRACTIONf_plane_restr0.0032385
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.9005-4.02640.50471360.46242743X-RAY DIFFRACTION95
4.0264-4.17030.40451420.39542704X-RAY DIFFRACTION95
4.1703-4.33720.33511470.33222753X-RAY DIFFRACTION95
4.3372-4.53460.32231310.2892717X-RAY DIFFRACTION95
4.5346-4.77370.29361450.25132707X-RAY DIFFRACTION95
4.7737-5.07280.26681460.242728X-RAY DIFFRACTION95
5.0728-5.46440.27031530.23452718X-RAY DIFFRACTION95
5.4644-6.01420.30741460.23442736X-RAY DIFFRACTION95
6.0142-6.88430.26881580.232710X-RAY DIFFRACTION94
6.8843-8.67260.20361450.20012749X-RAY DIFFRACTION95
8.6726-95.99920.23251390.20822753X-RAY DIFFRACTION95

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