Computational Modeling of the Anti-Inflammatory Complexes of IL37

Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, particularly through interfering with the IL18 signaling pathway, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune cancers and disorders. Although the structural homology between IL37 and IL18 suggests a common binding mechanism with the primary members, particularly receptors, of IL18 signaling, the structures of IL37 complexes have not been experimentally resolved yet. The structure and dynamics of IL37 complexes holds a substantial role offering molecular insights into IL37’s inhibitory function within the IL18 signaling pathway and informing future experimental research.

Study Overview: The study conducted by Sardag, Inci, et al., aimed to address the structural gap in lack of IL37 complexes through molecular modeling and classical molecular dynamics simulations, revealing the structural underpinnings of its modulatory effects on the IL18 signaling pathway thus understanding its anti-inflammatory role.

Materials and Methods: All IL37 protein-protein complexes, including both receptor dependent and receptor-independent pairs, were modeled using a range of methods from homology modeling to AlphaFold2 multimer predictions. The models that successfully captured experimental features were subjected to classical molecular dynamics simulations. As positive controls, binary and ternary PDB complexes of IL18 were also included.

Results
Dynamic nature of IL37 complexes: The comparative look on the IL37 and IL18 complexes revealed the high dynamism of IL37 complexes compared to that of IL18, supporting the relatively lower affinity of IL37 towards IL18 receptors.

IL37 dimer binding to IL18Rα: Repeated simulations of IL37-IL18Rα showed altered receptor conformations capable of accommodating IL37 in its dimeric form without clashes, providing a structural basis for the failure of IL18Rβ to be recruited to the IL37-IL18Rα complex.

Contribution of IL37 N-terminal loop: Simulations of receptor complexes involving different IL37 mature forms revealed that the N-terminal loop of IL37 is pivotal in modulating receptor dynamics. Additionally, the glycosyl chains on the primary receptor, IL18Rα, residue N297 act as a steric block against the IL37’s N-terminal loop.

Different binding modes of IL18BP with IL37 and IL18: Our dynamical models indicated that a homologous binding mode was unlikely, suggesting an alternative mechanism by which IL37 functions as an anti-inflammatory cytokine upon binding to IL18BP.

Discussion: Docking and AF2 multimer predictions failed to capture the experimentally relevant binding mode IL37 with IL18 partners. Therefore, leveraging the structural resemblance, IL37-receptor complexes were constructed based on IL18 homology. Another member of the IL1 family (IL1β) and its antagonist ( IL1RA) further validated the predicted IL37 binding mode, despite the low sequence similarity between IL18 and IL37 (∼20%).

Altered conformations of the N– and C-terminal lobes of the receptor α blocks formation of the IL37 ternary complex with an intact receptor β, however the IL37 binary complex is feasible, but it could with a shorter receptor that possesses only single domain. This explains the involvement of the SIGIRR receptor in the ternary anti-inflammatory complex of IL37. The positioning of the N-terminal loop of IL37 at the primary receptor interface along with interaction with the glycosyl chain on the receptor supports different signaling responses of IL37 mature forms with varying N-terminal lengths.

Conclusion: IL37 structurally replaces IL18 from its receptor complexes blocking IL18-induced inflammation and anti-inflammatory role of IL37 can even be structurally achieved in its dimeric form similarly through interfering with the IL18 signaling. Further validation of IL37 complexes was required to fully cover its anti-inflammatory response, however, this is thought to be challenging due to its lower affinity towards IL18 receptors.

Implications for Clinical Practice: Assessing structure and dynamics of IL37 complexes offers molecular insights into IL37’s inhibitory function within the IL18 signaling pathway and informs future structural experimental research. Uncovering IL37 complex structures is essential for the rational design of IL37 variants and drugs to block IL18-related inflammatory disease such as inflammatory bowel disease (IBD).

References:
Sardag, I., Duvenci, Z. S., Belkaya, S., & Timucin, E. (2024, September 21). Computational Modeling of the Anti-Inflammatory Complexes of IL37. bioRxiv. 10.1101/2024.09.21.613817