Structural characterisation of a spontaneous site 1 opening event in the insulin receptor
Stange, A. D.; Duncan, A. L.
Show abstract
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.
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