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- EMDB-36754: SLC15A4 inhibitor complex -

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Basic information

Entry
Database: EMDB / ID: EMD-36754
TitleSLC15A4 inhibitor complex
Map data
Sample
  • Organelle or cellular component: endolysosomal transporter
    • Protein or peptide: lysosomal transporter,ALFA tag,lysosomal transporter
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: 2-(4-ethoxyphenyl)-N-[3-[(2R)-2-methylpiperidin-1-yl]propyl]quinoline-4-carboxamide
Keywordsendolysosomal 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 / peptidoglycan transport / Proton/oligopeptide cotransporters / positive regulation of toll-like receptor 8 signaling pathway / regulation of isotype switching to IgG isotypes / 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 / peptidoglycan transport / Proton/oligopeptide cotransporters / positive regulation of toll-like receptor 8 signaling pathway / regulation of isotype switching to IgG isotypes / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway / dipeptide import across plasma membrane / positive regulation of toll-like receptor 7 signaling pathway / peptide:proton symporter activity / dipeptide transmembrane transporter activity / positive regulation of toll-like receptor 9 signaling pathway / 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 / specific granule membrane / monoatomic ion transport / protein transport / early endosome membrane / lysosomal membrane / innate immune response / Neutrophil degranulation / membrane / plasma membrane
Similarity search - Function
PTR2 family proton/oligopeptide symporters signature 2. / PTR2 family proton/oligopeptide symporter, conserved site / Proton-dependent oligopeptide transporter family / POT family / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier family 15 member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.5 Å
AuthorsZhang SS / Chen XD / Xie M
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21532004, 31570733 China
CitationJournal: 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
DepositionJul 6, 2023-
Header (metadata) releaseSep 27, 2023-
Map releaseSep 27, 2023-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36754.png

Downloads & links

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Map

FileDownload / File: emd_36754.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.8433 Å
Density
Contour LevelBy AUTHOR: 0.288
Minimum - Maximum-1.362597 - 2.521068
Average (Standard dev.)-0.0009690317 (±0.057707477)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 269.856 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36754_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36754_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : endolysosomal transporter

EntireName: endolysosomal transporter
Components
  • Organelle or cellular component: endolysosomal transporter
    • Protein or peptide: lysosomal transporter,ALFA tag,lysosomal transporter
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
  • Ligand: 2-(4-ethoxyphenyl)-N-[3-[(2R)-2-methylpiperidin-1-yl]propyl]quinoline-4-carboxamide

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Supramolecule #1: endolysosomal transporter

SupramoleculeName: endolysosomal transporter / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: lysosomal transporter,ALFA tag,lysosomal transporter

MacromoleculeName: lysosomal transporter,ALFA tag,lysosomal transporter / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.274246 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEGSGGGAGE RAPLLGARRA AAAAAAAGAF AGRRAACGAV LLTELLERAA FYGITSNLVL FLNGAPFCWE GAQASEALLL FMGLTYLGS PFGGWLADAR LGRARAILLS LALYLLGMLA FPLLAAPATR AALCGSARLL NCTAPGPDAA ARCCSPATFA G LVLVGLGV ...String:
MEGSGGGAGE RAPLLGARRA AAAAAAAGAF AGRRAACGAV LLTELLERAA FYGITSNLVL FLNGAPFCWE GAQASEALLL FMGLTYLGS PFGGWLADAR LGRARAILLS LALYLLGMLA FPLLAAPATR AALCGSARLL NCTAPGPDAA ARCCSPATFA G LVLVGLGV ATVKANITPF GADQVKDRGP EATRRFFNWF YWSINLGAIL SLGGIAYIQQ NVSFVTGYAI PTVCVGLAFV VF LCGQSVF ITKPPSRLEE ELRRRLTEGG PFTEEKVEDV KALVKIVPVF LALIPYWTVY FQMQTTYVLQ SLHLRIPEIS NIT TTPHTL PAAWLTMFDA VLILLLIPLK DKLVDPILRR HGLLPSSLKR IAVGMFFVMC SAFAAGILES KRLNLVKEKT INQT IGNVV YHAADLSLWW QVPQYLLIGI SEIFASIAGL EFAYSAAPKS MQSAIMGLFF FFSGVGSFVG SGLLALVSIK AIGWM SSHT DFGNINGCYL NYYFFLLAAI QGATLLLFLI ISVKYDHHRD HQRSRANGVP TSRRAGSLEV LFQGPGGGSG GGSWSH PQF EKGGGSGGGS WSHPQFEK

UniProtKB: Solute carrier family 15 member 4, Solute carrier family 15 member 4

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #4: 2-(4-ethoxyphenyl)-N-[3-[(2R)-2-methylpiperidin-1-yl]propyl]quino...

MacromoleculeName: 2-(4-ethoxyphenyl)-N-[3-[(2R)-2-methylpiperidin-1-yl]propyl]quinoline-4-carboxamide
type: ligand / ID: 4 / Number of copies: 2 / Formula: Q09
Molecular weightTheoretical: 431.57 Da
Chemical component information

ChemComp-Q09:
2-(4-ethoxyphenyl)-N-[3-[(2R)-2-methylpiperidin-1-yl]propyl]quinoline-4-carboxamide

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 12000

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