The signalling conformation of the insulin receptor ectodomain

Felix Weis, John G. Menting, Mai B. Margetts, Shu Jin Chan, Yibin Xu, Norbert Tennagels, Paulus Wohlfart, Thomas Langer, Christoph W. Müller (), Matthias K. Dreyer () and Michael C. Lawrence ()
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Felix Weis: Structural and Computational Biology Unit
John G. Menting: The Walter and Eliza Hall Institute of Medical Research
Mai B. Margetts: The Walter and Eliza Hall Institute of Medical Research
Shu Jin Chan: University of Chicago
Yibin Xu: The Walter and Eliza Hall Institute of Medical Research
Norbert Tennagels: TA Diabetes and Integrated Drug Discovery
Paulus Wohlfart: TA Diabetes and Integrated Drug Discovery
Thomas Langer: TA Diabetes and Integrated Drug Discovery
Christoph W. Müller: Structural and Computational Biology Unit
Matthias K. Dreyer: TA Diabetes and Integrated Drug Discovery
Michael C. Lawrence: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract Understanding the structural biology of the insulin receptor and how it signals is of key importance in the development of insulin analogs to treat diabetes. We report here a cryo-electron microscopy structure of a single insulin bound to a physiologically relevant, high-affinity version of the receptor ectodomain, the latter generated through attachment of C-terminal leucine zipper elements to overcome the conformational flexibility associated with ectodomain truncation. The resolution of the cryo-electron microscopy maps is 3.2 Å in the insulin-binding region and 4.2 Å in the membrane-proximal region. The structure reveals how the membrane proximal domains of the receptor come together to effect signalling and how insulin’s negative cooperativity of binding likely arises. Our structure further provides insight into the high affinity of certain super-mitogenic insulins. Together, these findings provide a new platform for insulin analog investigation and design.

Date: 2018
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DOI: 10.1038/s41467-018-06826-6

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