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- PDB-7t6f: Structure of active Janus Kinase (JAK) dimer complexed with cytok... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7t6f | ||||||||||||
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Title | Structure of active Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain | ||||||||||||
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![]() | SIGNALING PROTEIN / signaling complex / Janus Kinase / JAK / oncogenic mutation / gain-of-function mutation / cytokine receptor | ||||||||||||
Function / homology | ![]() response to type III interferon / interleukin-28 receptor complex / Interleukin-20 family signaling / mucosal immune response / positive regulation of cellular respiration / protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / positive regulation of homotypic cell-cell adhesion / interleukin-9-mediated signaling pathway ...response to type III interferon / interleukin-28 receptor complex / Interleukin-20 family signaling / mucosal immune response / positive regulation of cellular respiration / protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / positive regulation of homotypic cell-cell adhesion / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / regulation of defense response to virus by host / interleukin-15-mediated signaling pathway / growth hormone receptor binding / cytokine receptor activity / interleukin-6-mediated signaling pathway / type I interferon-mediated signaling pathway / positive regulation of sprouting angiogenesis / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / endomembrane system / type II interferon-mediated signaling pathway / extrinsic component of cytoplasmic side of plasma membrane / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / protein phosphatase binding / defense response to virus / cell differentiation / cytoskeleton / intracellular signal transduction / phosphorylation / response to antibiotic / ubiquitin protein ligase binding / ATP binding / nucleus / cytosol Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å | ||||||||||||
![]() | Glassman, C.R. / Tsutsumi, N. / Jude, K.M. / Garcia, K.C. | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation. Authors: Caleb R Glassman / Naotaka Tsutsumi / Robert A Saxton / Patrick J Lupardus / Kevin M Jude / K Christopher Garcia / ![]() Abstract: Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure of full- ...Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure of full-length JAK1 complexed with a cytokine receptor intracellular domain Box1 and Box2 regions captured as an activated homodimer bearing the valine→phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains of JAK1 form an extended structural unit, the dimerization of which is mediated by close-packing of the pseudokinase (PK) domains from the monomeric subunits. The oncogenic VF mutation lies within the core of the JAK1 PK interdimer interface, enhancing packing complementarity to facilitate ligand-independent activation. The carboxy-terminal tyrosine kinase domains are poised for transactivation and to phosphorylate the receptor STAT (signal transducer and activator of transcription)-recruiting motifs projecting from the overhanging FERM (four-point-one, ezrin, radixin, moesin)-SH2 (Src homology 2)-domains. Mapping of constitutively active JAK mutants supports a two-step allosteric activation mechanism and reveals opportunities for selective therapeutic targeting of oncogenic JAK signaling. | ||||||||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 394.5 KB | Display | ![]() |
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PDB format | ![]() | 311.8 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.7 MB | Display | ![]() |
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Full document | ![]() | 1.7 MB | Display | |
Data in XML | ![]() | 70.6 KB | Display | |
Data in CIF | ![]() | 104.6 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 25715MC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 136026.844 Da / Num. of mol.: 2 / Mutation: V657F Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: B1ASP2, non-specific protein-tyrosine kinase #2: Protein | Mass: 9895.373 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #3: Chemical | #4: Chemical | Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: GCN4-zippered dimeric IFN-lambda intracellular domain bound to two Jak1s Type: COMPLEX Details: Co-expressed GST-fused GCN4-IFN-lambda and full-length Jak1 in T. ni. GST tagged was removed by 3C protease digestion. Entity ID: #1-#2 / Source: RECOMBINANT | ||||||||||||||||||||||||
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Molecular weight | Value: 0.29 MDa / Experimental value: NO | ||||||||||||||||||||||||
Source (natural) | Organism: ![]() ![]() | ||||||||||||||||||||||||
Source (recombinant) | Organism: ![]() | ||||||||||||||||||||||||
Buffer solution | pH: 8 / Details: additive: 0.01% w/v DDM | ||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: GCN4-mIFN-lambda-box1box2-mJak1 V657F | ||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||||||||||
Vitrification | Instrument: LEICA EM GP / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 293 K / Details: 3 s blotting before plunging |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 29000 X / Calibrated magnification: 58680 X / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 55 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 29467 |
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Processing
Software | Name: PHENIX / Version: 1.19.2_4158: / Classification: refinement | ||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Details: Final per-particle CTF values were determined by cryoSPARC Local CTF Refinement. Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 17057371 Details: Including non-proteinous features. The actual number of intact complex particles was ~1,429,325. | ||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 224615 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT / Space: REAL | ||||||||||||||||||||||||||||||||
Refine LS restraints |
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