Structural characterisation of a spontaneous site 1 opening event in the insulin receptor

The insulin receptor samples multiple conformational states during ligand binding and activation, but the transient structural transitions connecting experimentally resolved receptor conformations remain poorly characterised. Here, we report a spontaneous opening event of insulin receptor site 1 observed during an unbiased molecular dynamics simulation initiated from the experimentally resolved singly insulin-bound IR1 receptor structure. The transition was characterised by separation of the L1 and FnIII-2 domains, rearrangement of site 1 contacts, and bending of the CT segment on the initially unoccupied receptor protomer. Structural comparison of the resulting conformation revealed similarity to the asymmetric IR2-A1 and IR2-A2 receptor states associated with hybrid insulin binding sites. Together, these findings suggest that conformations compatible with hybrid-site receptor states can emerge spontaneously from the intrinsic dynamics of the insulin receptor ectodomain, supporting a conformational selection model for receptor ligand engagement.