Antagonist Binding Actively Disrupts Interleukin-1 Receptor Dynamics to Block Co-receptor Recruitment

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Interleukin-1 receptor type 1 (IL1R1) regulates inflammatory signaling.
• Understanding how agonists and antagonists yield opposite outcomes at the same binding site is unclear.
• Existing structural data lack dynamic insights into antagonist inhibition.

Purpose of the Study:

• To investigate the dynamic mechanisms underlying IL1R1 activation and antagonism.
• To compare the intrinsic dynamics of IL1R1 in unbound, agonist-bound, antagonist-bound, and co-receptor-bound states.
• To elucidate how antagonists prevent co-receptor recruitment.

Main Methods:

• All-atom molecular dynamics simulations.
• Multiscale flexibility modeling using CABS-flex.
• Systematic comparison of IL1R1 dynamics across different binding states.

Main Results:

• Both agonists and antagonists bind the same IL1R1 interface but induce distinct dynamic responses.
• Agonist binding stabilizes interdomain coupling, promoting a signaling-competent state.
• Antagonist binding increases D3 domain flexibility at the co-receptor interface, blocking activation.

Conclusions:

• IL1R1 antagonism is an active, allosteric, dynamics-driven process.
• Receptor dynamics are crucial for controlling IL1R1 signaling outcomes.
• This study provides a mechanistic framework reconciling structural and functional data.