NACHT, LRR and PYD domains-containing protein 3 (NLRP3)–NIMA-related kinase 7 (NEK7) protein–protein interaction (NLRP3–NEK7 interaction)

The NLRP3–NEK7 protein–protein interaction is a critical regulatory checkpoint in the assembly and activation of the NLRP3 inflammasome, a multi-protein complex of the innate immune system (He et al., Nature, 2016). NEK7, a serine/threonine kinase previously known for its role in mitosis, functions as an essential scaffold that binds to the leucine-rich repeat (LRR) and NACHT domains of NLRP3 (Sharif et al., Nature, 2019). This binding event is required for NLRP3 to undergo the conformational changes necessary for oligomerization and the subsequent recruitment of the adapter protein ASC. Without the interaction with NEK7, NLRP3 remains in an inactive state, preventing the activation of caspase-1 and the maturation of pro-inflammatory cytokines such as IL-1β and IL-18. Pathological overactivation of this interaction is implicated in numerous inflammatory diseases, including gout, atherosclerosis, type 2 diabetes, and neurodegenerative conditions like Alzheimer's disease. Consequently, the NLRP3–NEK7 interface has emerged as a high-priority therapeutic target. Small-molecule inhibitors, such as Oridonin and CY-09, have been shown to specifically disrupt this interaction, offering a targeted approach to treat chronic inflammatory disorders by preventing inflammasome-mediated tissue damage (He et al., Nat Commun, 2018; Jiang et al., J Exp Med, 2017).

Other names

NLRP3-NEK7 complexNLRP3-NEK7 binding interfaceNEK7-NLRP3 inflammasome module

Small-molecule inhibition of the physical binding between the NEK7 C-terminal catalytic domain and the NLRP3 LRR/NACHT domains, preventing the conformational transition required for NLRP3 oligomerization and ASC recruitment (Sharif et al., Nature, 2019; He et al., Nat Commun, 2018).