Multiscale computational elucidation of Interleukin-17 receptor A-E3 ubiquitin ligase TRAF3IP2 signaling nexus: structural dynamics and hotspots for targeted autoimmune and anti-inflammatory therapeutics.

Autoimmune and inflammatory diseases represent a growing global health burden, with the IL-17 signaling pathway emerging as a prime therapeutic target. The protein-protein interaction between IL-17 receptor A (IL-17RA) and its adaptor ACT1 is central to pathogenic inflammation, yet remains structurally uncharacterized, limiting rational drug design efforts. The absence of high-resolution crystal structures for therapeutically relevant IL-17RA-ACT1 interactions poses a fundamental bottleneck in structure-based drug discovery. We address this critical knowledge gap through comprehensive computational analysis, revealing for the first time that IL-17RA-ACT1 binding operates via a sophisticated three-phase mechanism involving initial fold recognition, conformational adaptation, and final SEFIR-SEFIR engagement rather than instantaneous association, that fundamentally redefine our understanding of SEFIR domain interactions. Integrating protein network analysis, molecular docking, and dynamics simulations, we demonstrate that IL-17RA serves as a rigid scaffold accommodating ACT1's conformational flexibility during complex assembly. Our findings reveal exceptional binding stability (ΔGbind = -43.63 ± 0.48 kcal/mol) and identify specific hotspot residues critical for initial protein recognition. Importantly, the dynamic opening of ACT1's SEFIR domain towards IL-17RA creates targetable conformational states previously invisible to structure-based drug design. This mechanistic understanding transforms our ability to rationally design small molecules and biologicals that can selectively disrupt pathogenic IL-17 signaling while preserving beneficial immune responses. Our computational framework offers a structural blueprints for developing targeted therapeutics against rheumatoid arthritis, psoriasis, inflammatory bowel disease, and other IL-17-driven pathologies that currently lack targeted treatment options.