Publication details
Peptidomimetics with full antagonistic effect stabilize insulin receptor in novel conformation
| Authors | |
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| Year of publication | 2024 |
| Type | Conference abstract |
| Citation | |
| Description | The human insulin receptor (IR) is one of the most studied receptor tyrosine kinases (RTKs). Binding of the signal molecule to the extracellular part of RTKs initiates receptor dimerization which triggers autophosphorylation on the intracellular part of the receptor. Unlike most RTKs, IR forms a disulfide bond stabilized dimer already in the apo-form. Therefore, an autoinhibitory mechanism must exist to prevent non-receptor activation of the signaling pathway. We have studied the structural changes of the insulin receptor ectodomain in vitro caused by 3 peptidomimetics: adamantane-derived mimetic (Ada), trimesic acid-derived mimetic (Trim) and S661, which were shown to be full insulin antagonists. We have used single particle electron cryo-microcopy (cryo-EM) to describe the mechanism of insulin receptor inhibition by these compounds. Our cryo-EM structures reveal that the studied antagonists cross-link L1 and FnIII-1’ domains of the insulin receptor, therefore stabilizing the ? shape structure in which membrane proximal regions of FnIII-3 and FnIII-3’ are separated by 115 A, thus preventing autophosphorylation in the intracellular domains of the receptor. The head of the dimer (L1 to FnIII-1’ and L1’ to FnIII-1) is wider than in the case of insulin-IR and forms a shape resembling goggles. Remarkably, we do not observe ?-CT helix densities in our cryo- EM maps. In addition, multiple interaction interfaces are observed between L1 and FnIII-2 domains which provide indication for elucidation of receptor activation mechanism. |