RESUMEN
Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family ß-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
Asunto(s)
Citocinas , Interleucina-11 , Humanos , Interleucina-11/genética , Receptor gp130 de Citocinas/genética , Interleucina-6/metabolismo , Antígenos CD/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Interleucina-6/metabolismoRESUMEN
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.
Asunto(s)
Antimaláricos , Malaria Falciparum , Terapia Molecular Dirigida , Plasmodium falciparum , Biosíntesis de Proteínas , Proteínas Protozoarias , Tirosina-ARNt Ligasa , Adenosina/análogos & derivados , Animales , Antimaláricos/química , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Cristalografía por Rayos X , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/enzimología , Biosíntesis de Proteínas/efectos de los fármacos , Conformación Proteica , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Ácidos Sulfónicos/química , Tirosina-ARNt Ligasa/química , Tirosina-ARNt Ligasa/metabolismoRESUMEN
Interleukin-11 (IL-11) is a cytokine that has been strongly implicated in the pathogenesis of fibrotic diseases and solid malignancies. Elevated IL-11 expression is also associated with several non-malignant inflammatory diseases where its function remains less well-characterized. Here, we summarize current literature surrounding the contribution of IL-11 to the pathogenesis of autoimmune inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, diabetes and systemic sclerosis, as well as other chronic inflammatory conditions such as periodontitis, asthma, chronic obstructive pulmonary disease, psoriasis and colitis.
