Interleukin-23 (IL-23), an IL-12 family cytokine, plays pivotal roles in pro-inflammatory T helper 17 cell responses linked to autoimmune and inflammatory diseases. Despite intense therapeutic targeting, structural and mechanistic insights into receptor complexes mediated by IL-23, and by IL-12 family members in general, have remained elusive. We determined a crystal structure of human IL-23 in complex with its cognate receptor, IL-23R, and revealed that IL-23R bound to IL-23 exclusively via its N-terminal immunoglobulin domain. The structural and functional hotspot of this interaction partially restructured the helical IL-23p19 subunit of IL-23 and restrained its IL-12p40 subunit to cooperatively bind the shared receptor IL-12Rβ1 with high affinity. Together with structural insights from the interaction of IL-23 with the inhibitory antibody briakinumab and by leveraging additional IL-23:antibody complexes, we propose a mechanistic paradigm for IL-23 and IL-12 whereby cognate receptor binding to the helical cytokine subunits primes recruitment of the shared receptors via the IL-12p40 subunit.

白介素23（IL-23），一种IL-12家族细胞因子，在与自身免疫性疾病和炎性疾病有关的促炎性T辅助17细胞反应中起关键作用。尽管有强烈的治疗靶向性，但对由IL-23和一般由IL-12家族成员介导的受体复合物的结构和机理的见解仍然难以捉摸。我们确定了人类IL-23及其同源受体IL-23R的晶体结构，并揭示了IL-23R仅通过其N末端免疫球蛋白结构域与IL-23结合。这种相互作用的结构和功能热点部分重组了IL-23的螺旋IL-23p19亚基，并限制了其IL-12p40亚基以高亲和力协同结合共享的受体IL-12Rβ1。