P140: Understanding the IFNÂ-IFNAR1 interface: implications for drug discovery in IFNÂ-DRIVEN disease [Poster Abstract]

We have previously shown that IFN-b can bind directly to IFNAR1, in the absence of IFNAR2, and can transmit a signal that contributes to lethality in a mouse model of sepsis1 . In this previous study we also determined the crystal structure of IFN-b bound to the extracellular domain (ECD) of IFNAR1, showing unique interaction interfaces not previously defined for other IFN-receptor complexes and enabling us to hypothesise a molecular basis for the higher binding affinity of IFN-b for IFNAR1 compared to other IFNs1 . In light of the structural and functional insights we have into this unique signaling complex, herein we sought to investigate the molecular determinants that influenced stability of the IFN-b/IFNAR1 complex and contributed to IFN-b driven signaling in an effort to inform drug discovery to antagonize this ligand-receptor interaction.