Grant: Travel Awards - Institute Community Support

For decades, X-ray crystallography has provided the foundational insights into cytokine signalling, offering high-resolution structures of cytokines and receptor ectodomains. These studies illuminated key principles of ligand-receptor recognition and receptor assembly, forming the basis for our molecular understanding of immune signalling. However, due to the dynamic and often transient nature of cytokine receptor complexes, many remained inaccessible to traditional crystallographic approaches. Cryo-electron microscopy (cryoEM) has transformed our ability to visualize these critical signalling assemblies in their native states, ushering in a new era of structural cytokine biology. We have now leveraged cryoEM to resolve many longstanding questions in cytokine signalling. Our structures of the IL-17 receptor complex provided the first molecular understanding of the ternary signalling complexes formed, outlining a key new role for IL-RA in signalling. Our IL-5 receptor structure overturned then current dogma, revealing signalling potentiated by hexameric receptor complex assembly. Our work on the leptin receptor captured the signalling conformation of this physiologically important receptor and laid the foundation for structure-guided engineering. Finally, our structural elucidation of JAK transactivation provided direct visualization of this key step in the activation of JAK-STAT signalling and potentiating further therapeutic discovery in this space. By integrating cryo-EM with functional studies and receptor engineering, we have provided unprecedented molecular insights into cytokine signalling mechanisms, many of which were previously inaccessible. This shift from crystallographic methodology to cryo-EM reconstruction is redefining the structural landscape of cytokine signalling, paving the way for a new wave of understanding in this space.