Cryo electron microscopy reveals new insights into how the insulin receptor binds insulin

The current understanding of how precisely insulin interacts with its receptor to trigger the cell’s response is incomplete. Scientists have now reconstructed a 3D map of the insulin receptor bound to insulin and could demonstrate how insulin binds to a second site on its receptor. Previous biochemical and genetic studies suggested the presence of a second binding site, however, unequivocal structural evidence was lacking. This obtained detailed knowledge of the binding process may contribute to develop new targeted therapies to treat diseases related to insulin malfunction or deficiencies such as diabetes, Alzheimer’s disease, and cancer.

Image: The insulin receptor with 4 insulin molecules. A 2D view of the insulin receptor ectodomain saturated with insulin obtained by cryo-electron microscopy (left), a 3D reconstruction (middle), and the corresponding scheme of the complete receptor (right). The insulin receptor ectodomain and the four insulins are colored in blue and red, respectively. © Gutmann, Schäfer, Poojari et al., Journal of Cell Biology (2019)

The biological actions of insulin are mediated by its binding to a specific membrane protein: the so-called insulin receptor, which is localized on the cell surface. To date, generating insulin analogs that mimic the full spectrum of insulin action in the human body remains challenging. The main problem is that the mechanism by which insulin interacts with its receptor to activate signal cascades inside the cell leading to sugar uptake from the blood among other effects, is incompletely understood.

To gain more insights into this process, scientists led by researchers from the Paul Langerhans Institute Dresden – a satellite of Helmholtz Zentrum München and partner of the German Center for Diabetes Research (DZD e.V.) – together with the Faculty of Medicine Carl Gustav Carus at TU Dresden, colleagues from the Max Planck Institute of Biochemistry in Munich, McGill University in Canada and the University of Helsinki studied the insulin-binding part of the insulin receptor by cryo-electron microscopy combined with molecular dynamics simulations. Cryo-electron microscopy is a powerful technique to visualize 3-dimensional structures of proteins.

Importantly, the scientists added insulin in excess to the insulin receptor to saturate all available binding sites. This approach enabled capturing the extracellular part of the receptor when all binding sites are occupied by insulin, which looks like a “T”. The binding of up to 4 insulin molecules to a single receptor at a time could be observed for the first time. It was proposed already more than 40 years ago that the insulin molecule has two distinct binding surfaces through which it can interact with its receptor, called “site 1” and “site 2”. While site 1 interactions have been demonstrated before, the existence of site 2 interactions remained highly controversial. With this recent study published in Journal of Cell Biology, scientists could finally demonstrate the structural basis of site 2 interactions. 

These details concerning insulin-receptor-interactions will ultimately expand the current models of insulin binding to its receptor and could pave the way towards new approaches to structure-based drug design for insulin-related diseases.

Original publication:
Gutmann T, Schäfer IB, Poojari C, Brankatschk B, Vattulainen I, Strauss M, Coskun Ü, 2019: Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain. Journal of Cell Biology, DOI: 10.1083/jcb.201907210

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