+Open data
-Basic information
Entry | Database: PDB / ID: 8jzx | |||||||||
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Title | SLC15A4 inhibitor complex | |||||||||
Components | lysosomal transporter,ALFA tag,lysosomal transporter | |||||||||
Keywords | PROTEIN TRANSPORT/INHIBITOR / endolysosomal transporter / PROTEIN TRANSPORT-INHIBITOR COMPLEX | |||||||||
Function / homology | Function and homology information L-histidine transmembrane transporter activity / histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / regulation of isotype switching to IgG isotypes / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway ...L-histidine transmembrane transporter activity / histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / regulation of isotype switching to IgG isotypes / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway / positive regulation of toll-like receptor 7 signaling pathway / dipeptide import across plasma membrane / peptide:proton symporter activity / positive regulation of toll-like receptor 9 signaling pathway / dipeptide transmembrane transporter activity / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / endolysosome membrane / positive regulation of innate immune response / peptide transport / specific granule membrane / monoatomic ion transport / protein transport / early endosome membrane / lysosomal membrane / innate immune response / Neutrophil degranulation / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) synthetic construct (others) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å | |||||||||
Authors | Zhang, S.S. / Chen, X.D. / Xie, M. | |||||||||
Funding support | China, 1items
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Citation | Journal: Nat Commun / Year: 2023 Title: A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity. Authors: Andras Boeszoermenyi / Léa Bernaleau / Xudong Chen / Felix Kartnig / Min Xie / Haobo Zhang / Sensen Zhang / Maeva Delacrétaz / Anna Koren / Ann-Katrin Hopp / Vojtech Dvorak / Stefan ...Authors: Andras Boeszoermenyi / Léa Bernaleau / Xudong Chen / Felix Kartnig / Min Xie / Haobo Zhang / Sensen Zhang / Maeva Delacrétaz / Anna Koren / Ann-Katrin Hopp / Vojtech Dvorak / Stefan Kubicek / Daniel Aletaha / Maojun Yang / Manuele Rebsamen / Leonhard X Heinz / Giulio Superti-Furga / Abstract: Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the ...Dysregulation of pathogen-recognition pathways of the innate immune system is associated with multiple autoimmune disorders. Due to the intricacies of the molecular network involved, the identification of pathway- and disease-specific therapeutics has been challenging. Using a phenotypic assay monitoring the degradation of the immune adapter TASL, we identify feeblin, a chemical entity which inhibits the nucleic acid-sensing TLR7/8 pathway activating IRF5 by disrupting the SLC15A4-TASL adapter module. A high-resolution cryo-EM structure of feeblin with SLC15A4 reveals that the inhibitor binds a lysosomal outward-open conformation incompatible with TASL binding on the cytoplasmic side, leading to degradation of TASL. This mechanism of action exploits a conformational switch and converts a target-binding event into proteostatic regulation of the effector protein TASL, interrupting the TLR7/8-IRF5 signaling pathway and preventing downstream proinflammatory responses. Considering that all components involved have been genetically associated with systemic lupus erythematosus and that feeblin blocks responses in disease-relevant human immune cells from patients, the study represents a proof-of-concept for the development of therapeutics against this disease. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8jzx.cif.gz | 170.2 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8jzx.ent.gz | 132.3 KB | Display | PDB format |
PDBx/mmJSON format | 8jzx.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8jzx_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 8jzx_full_validation.pdf.gz | 1.5 MB | Display | |
Data in XML | 8jzx_validation.xml.gz | 40.5 KB | Display | |
Data in CIF | 8jzx_validation.cif.gz | 56 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/jz/8jzx ftp://data.pdbj.org/pub/pdb/validation_reports/jz/8jzx | HTTPS FTP |
-Related structure data
Related structure data | 36754MC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 62274.246 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others) Gene: SLC15A4 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8N697 #2: Sugar | #3: Chemical | ChemComp-CLR / #4: Chemical | Has ligand of interest | Y | |
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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 |
-Sample preparation
Component | Name: endolysosomal transporter / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.2 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-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: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 12000 / Symmetry type: POINT |