Symmetric and asymmetric receptor conformation continuum induced by a new 
insulin

Xiong, Xiaochun; Blakely, Alan; Kim, Jin Hwan; Menting, John G.; Schäfer, Ingmar B.; Schubert, Heidi L.; Agrawal, Rahul; Gutmann, Theresia; Delaine, Carlie; Zhang, Yi Wolf; Artik, Gizem Olay; Merriman, Allanah; Eckert, Debbie; Lawrence, Michael C.; Coskun, Uenal; Fisher, Simon J.; Forbes, Briony E.; Safavi-Hemami, Helena; Hill, Christopher P.; Chou, Danny Hung-Chieh

doi:10.1038/s41589-022-00981-0

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Symmetric and asymmetric receptor conformation continuum induced by a new insulin

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Schäfer, Ingmar B.
Conti, Elena / Structural Cell Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Xiong, X., Blakely, A., Kim, J. H., Menting, J. G., Schäfer, I. B., Schubert, H. L., et al. (2022). Symmetric and asymmetric receptor conformation continuum induced by a new insulin. Nature Chemical Biology, 18, 511-519. doi:10.1038/s41589-022-00981-0.

Cite as: https://hdl.handle.net/21.11116/0000-000A-2AD6-6

Abstract

Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions.