https://biblio.ugent.be/ Ghent University Academic Bibliography 2000-01-01T00:00+00:00 1 monthly https://biblio.ugent.be/publication/01HS0JG3FYZ3FBWHXYP670TEFK Bloch, Yehudi Félix, Jan Merceron, Romain Provost, Mathias Alipour Symakani, Royan De Backer, Robin Lambert, Elisabeth Mehdipour, Ahmadreza Savvides, Savvas 2024 Cell-surface receptor complexes mediated by pro-inflammatory interleukin (IL)-12 and IL-23, both validated therapeutic targets, are incompletely understood due to the lack of structural insights into their complete extracellular assemblies. Furthermore, there is a paucity of structural details describing the IL-12-receptor interaction interfaces, in contrast to IL-23-receptor complexes. Here we report structures of fully assembled mouse IL-12/human IL-23-receptor complexes comprising the complete extracellular segments of the cognate receptors determined by electron cryo-microscopy. The structures reveal key commonalities but also surprisingly diverse features. Most notably, whereas IL-12 and IL-23 both utilize a conspicuously presented aromatic residue on their alpha-subunit as a hotspot to interact with the N-terminal Ig domain of their high-affinity receptors, only IL-12 juxtaposes receptor domains proximal to the cell membrane. Collectively, our findings will help to complete our understanding of cytokine-mediated assemblies of tall cytokine receptors and will enable a cytokine-specific interrogation of IL-12/IL-23 signaling in physiology and disease. Structures of complete extracellular receptor assemblies mediated by the pro-inflammatory cytokines IL-12 and IL-23 reveal key commonalities and diverse features, with only IL-12 juxtaposing receptor domains proximal to the cell membrane. application/pdf https://biblio.ugent.be/publication/01HS0JG3FYZ3FBWHXYP670TEFK http://hdl.handle.net/1854/LU-01HS0JG3FYZ3FBWHXYP670TEFK http://doi.org/10.1038/s41594-023-01190-6 https://biblio.ugent.be/publication/01HS0JG3FYZ3FBWHXYP670TEFK/file/01HS0WZCFY27FXBDC2N0K76SXD eng info:eu-repo/semantics/openAccess NATURE STRUCTURAL & MOLECULAR BIOLOGY ISSN: 1545-9993 ISSN: 1545-9985 Biology and Life Sciences PARTICLE CRYO-EM MOLECULAR-DYNAMICS HETERODIMERIC CYTOKINE ORIENTATION DISTINCT SUBUNIT REVEALS SYSTEM Structures of complete extracellular receptor assemblies mediated by IL-12 and IL-23 journalArticle info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion