Abstract
IL37 plays important roles in the regulation of innate immunity and its oligomeric status is critical to these roles. In its monomeric state, IL37 can effectively inhibit the inflammatory response of IL18 by binding to IL18R
α
, a capacity lost in its dimeric form, underlining the pivotal role of the oligomeric status of IL37 in its anti-inflammatory action. Until now, two IL37 dimer structures have been deposited in PDB, reflecting a substantial difference in their dimer interfaces. Given this discrepancy, we analyzed the PDB structures of the IL37 dimer (PDB IDs:
6ncu
,
5hn1
) along with a AF2-multimer prediction by molecular dynamics (MD) simulations. Results showed that the
5hn1
and AF2-predicted dimers have the same interface and stably maintained their conformations throughout simulations, while the recent IL37 dimer (PDB ID:
6ncu
) with a different interface did not, proposing a possible issue with the recent IL37 dimer structure (
6ncu
). Next, focusing on the stable dimer structures, we have identified five critical positions of V71/Y85/I86/E89/S114, three new positions compared to the literature, that would reduce dimer stability without affecting the monomer structure. Two quintuple mutants were tested by MD simulations and showed partial or complete dissociation of the dimer. Overall, the insights gained from this study reinforce the validity of the
5hn1
and AF2 multimer structures, while also advancing our understanding of the IL37 dimer interface through the generation of monomer-locked IL37 variants.