CCeMMP Seminar Series A/Prof Michael Griffin – April 2023

Structures of the interleukin 11 signalling complex reveal dynamics of gp130 extracellular domains and a surprising inhibitory mechanism of a cytokine variant

Interleukin 11 (IL-11), an IL-6 family cytokine, plays pivotal roles in many autoimmune diseases, fibrotic complications, and solid cancers. IL-11 activates downstream signalling pathways by binding its two cell-surface receptors; the IL-11 specific receptor, IL-11Rα, and the shared IL-6 family signal-transducing receptor, glycoprotein 130 (gp130). Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors remain limited. Here Associate Professor Griffin presents cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of gp130. He shows that complex formation requires conformational reorganisation of IL-11, which is coordinated by a key arginine residue, R169 and also shows that the membrane-proximal domains of gp130 are dynamic and do not participate directly in signalling complex formation. He demonstrates that the cytokine mutant ‘IL-11 Mutein’ competitively inhibits IL-11 signalling in human cell lines. Structural shifts in IL-11 Mutein, caused by altered dynamics of a large loop region, underlie signalling inhibition. These structural alterations modulate cytokine binding interactions at all three receptor-engaging sites of the cytokine, including abrogating the final gp130 binding step. The results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of receptor dynamics in gp130-containing receptor complexes. These insights provide invaluable molecular platforms for development of existing and novel therapeutics targeting IL-11 signalling and signalling by other class I cytokines.

A/Prof Michael Griffin

Department of Biochemistry and Pharmacology,

Bio21 Molecular Science and Biotechnology Institute,

The University of Melbourne