Cytokines are important signalling molecules which can cause inflammation, regulate haematopoiesis and modulate the immune response. Over 50 cytokines achieve their biological functions on cells via the JAK/STAT pathway. SOCS (Suppressors of Cytokine Signalling) family are induced by the cytokine-JAK-STAT cascade and act as negative feedback regulators to specific cytokine pathway. The existence of the SOCS family prevents cells from persistent activation of cytokine signalling but can also play a role in cytokine resistance and tumour progression.
SOCS1, a member of SOCS family, is specifically induced by IFN-gamma. The SH2 domain and the KIR domain are critical for SOCS1’s function. The SH2 domain is responsible for protein-protein interactions by specifically targeting pTyr-containing substrates. However, the structural details of the SOCS1 SH2 domain interacting with its targets and how this interaction happens in vivo remained unclear. Our work determined the crystal structures of SOCS1 SH2 domain bound to various ligands, which uncovered the molecular interactions within this domain. Additionally, small molecules with potentially high affinity for targeting the SOCS1 SH2 domain were identified through structure-guided drug design.
The KIR domain of SOCS1 can insert into the substrate-binding pocket and directly inhibit the catalytic activity of JAK1. Our research also attempted to develop novel type of JAK inhibitors based on the binding mechanism of KIR domain.
These findings provided insights into the interactions between JAK and SOCS1 and also highlighted the potential of developing small molecules to disrupt these interactions.