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... More
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.
