インターロイキン-37: 炎症コントロールの鍵となる存在

タイトル: Rational Design of Monomeric IL37 Variants Guided by Stability and Dynamical Analyses of IL37 Dimers

概要: 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 triggered by IL18 through binding to the IL18 receptor , a capability lost in its dimeric form. This paradigm underscores the pivotal role of IL37s dimer structure in the design of novel anti-inflammatory therapeutics. Hitherto, two IL37 dimer structures were deposited in PDB, reflecting the potential use of their binding interface in the design of IL37 variants with altered dimerization tendencies. Inspection of these static structures suggested a substantial difference in their dimer interfaces. Prompted by this discrepancy, we analyzed the PDB structures of IL37 dimer (PDB: 6ncu and 5hn1) along with a predicted structure by AF2-multimer by molecular dynamics (MD) simulations to unravel whether and how IL37 can form homodimers through distinct interfaces. Results showed that the 5hn1 and AF2 dimers, which shared the same interface, stably maintained their initial conformations throughout the simulations whilst the recent IL37 dimer (PDB ID: 6ncu) with a different interface, did not. These findings underscored that the recent IL37 dimer (6ncu) structure is likely to contain an error, probably in its biological assembly record, otherwise it was not a stable assembly in silico. Next, focusing on the stable dimer structure of 5hn1, we have identified five critical positions of V71/Y85/I86/E89/S114 that would altogether reduce dimer stability without affecting the monomer fold. Two quintet mutations were tested similarly by MD simulations and both mutations showed either partial or complete dissociation of the dimeric form. Overall, this work contributes to the development of IL37-based therapeutics by accurately representing the dimer interface in the PDB structures and identifying five potential substitutions to effectively inhibit the inflammatory response triggered by IL18.