Antagonist binding actively disrupts interleukin-1 receptor dynamics to block co-receptor recruitment

The interleukin-1 receptor type 1 (IL1R1) is a central regulator of inflammatory signaling and functions as a molecular switch, yet it remains unclear how agonists and antagonists that bind the same primary site produce opposite signaling outcomes. Available structural data define inactive and active endpoint conformations but do not explain how antagonist binding dynamically prevents co-receptor recruitment. Here, we combine all-atom molecular dynamics simulations with multiscale flexibility modeling using CABS-flex to systematically compare the intrinsic dynamics of IL1R1 across its unbound, agonist-bound, antagonist-bound, and co-receptor-bound states. Although both agonists and antagonists engage the same conserved interface on the D1/D2 domains, they induce fundamentally different dynamic responses in the receptor. Agonist binding progressively stabilizes interdomain coupling and promotes a stepwise transition toward a signaling-competent conformation. In contrast, antagonist binding selectively increases flexibility of the distal D3 domain, particularly at the co-receptor binding interface, thereby preventing progression along the activation pathway. Importantly, the interaction patterns and dynamic signatures observed in the simulations are consistent with experimentally identified binding determinants, mutational data, and structural features associated with receptor activation and inhibition. These results demonstrate that IL1R1 antagonism is an active, allosteric, dynamics-driven process rather than a simple failure to stabilize an active conformation. Together, this work provides a mechanistic framework that reconciles existing structural and functional observations and highlights receptor dynamics as a key determinant of signaling control in the interleukin-1 system.