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TitleA conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 6626, Year 2023
Publish dateOct 20, 2023
AuthorsAndras 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 /
PubMed AbstractDysregulation 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.
External linksNat Commun / PubMed:37863876 / PubMed Central
MethodsEM (single particle)
Resolution2.5 Å
Structure data

36754

8jzx

EMDB-36754, PDB-8jzx:
SLC15A4 inhibitor complex
Method: EM (single particle) / Resolution: 2.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CLR:
CHOLESTEROL

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

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsPROTEIN TRANSPORT/INHIBITOR / endolysosomal transporter / PROTEIN TRANSPORT-INHIBITOR COMPLEX

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