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- PDB-7t6f: Structure of active Janus Kinase (JAK) dimer complexed with cytok... -

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Basic information

Entry
Database: PDB / ID: 7t6f
TitleStructure of active Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain
Components
  • Interferon lambda receptor 1
  • Tyrosine-protein kinase
KeywordsSIGNALING PROTEIN / signaling complex / Janus Kinase / JAK / oncogenic mutation / gain-of-function mutation / cytokine receptor
Function / homology
Function and homology information


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 / cytokine receptor activity / growth hormone receptor binding / type I interferon-mediated signaling pathway / interleukin-6-mediated signaling pathway / positive regulation of sprouting angiogenesis / extrinsic component of cytoplasmic side of plasma membrane / cell surface receptor signaling pathway via JAK-STAT / endomembrane system / type II interferon-mediated signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / defense response to virus / protein phosphatase binding / cytoskeleton / intracellular signal transduction / response to antibiotic / ubiquitin protein ligase binding / ATP binding / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak1 / : / Tissue factor / SH2 domain / 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 ...Tyrosine-protein kinase, non-receptor Jak1 / : / Tissue factor / SH2 domain / 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 central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
Similarity search - Domain/homology
ADENOSINE / ADENOSINE-5'-DIPHOSPHATE / Tyrosine-protein kinase / Interferon lambda receptor 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsGlassman, C.R. / Tsutsumi, N. / Jude, K.M. / Garcia, K.C.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R37AI051321 United States
Howard Hughes Medical Institute (HHMI) United States
Ludwig Institute for Cancer Research (LICR) United States
CitationJournal: Science / Year: 2022
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
DepositionDec 13, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 16, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Apr 20, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Feb 28, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

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Assembly

Deposited unit
A: Tyrosine-protein kinase
C: Interferon lambda receptor 1
D: Interferon lambda receptor 1
B: Tyrosine-protein kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)293,2338
Polymers291,8444
Non-polymers1,3894
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Tyrosine-protein kinase


Mass: 136026.844 Da / Num. of mol.: 2 / Mutation: V657F
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Jak1 / Variant: V657F / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: B1ASP2, non-specific protein-tyrosine kinase
#2: Protein Interferon lambda receptor 1 / IFN-lambda R1 / Cytokine receptor class-II member 12 / Cytokine receptor family 2 member 12 / CRF2- ...IFN-lambda R1 / Cytokine receptor class-II member 12 / Cytokine receptor family 2 member 12 / CRF2-12 / Interleukin-28 receptor subunit alpha / IL-28 receptor subunit alpha / IL-28R-alpha / IL-28RA


Mass: 9895.373 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ifnlr1, Il28ra / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8CGK5
#3: Chemical ChemComp-ADN / ADENOSINE


Mass: 267.241 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H13N5O4
#4: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 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
Molecular weightValue: 0.29 MDa / Experimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 8 / Details: additive: 0.01% w/v DDM
Buffer component
IDConc.NameBuffer-ID
120 mMHepes-sodium salt1
2500 mMsodium chloride1
31 % w/vglycerol1
41 mMadenosine1
51 mMTCEP1
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: GCN4-mIFN-lambda-box1box2-mJak1 V657F
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: 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
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: 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 holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron 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

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
4cryoSPARC3.3CTF correction
9PHENIXmodel refinement
10cryoSPARC3.3initial Euler assignment
11cryoSPARC3.3final Euler assignment
12cryoSPARC3.3classification
13cryoSPARC3.33D reconstruction
CTF correctionDetails: Final per-particle CTF values were determined by cryoSPARC Local CTF Refinement.
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 17057371
Details: Including non-proteinous features. The actual number of intact complex particles was ~1,429,325.
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 224615 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00317462
ELECTRON MICROSCOPYf_angle_d0.4723692
ELECTRON MICROSCOPYf_dihedral_angle_d10.1076356
ELECTRON MICROSCOPYf_chiral_restr0.042630
ELECTRON MICROSCOPYf_plane_restr0.0033030

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