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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Weis F,Menting JG,Margetts MB,Chan SJ,Xu Y,Tennagels N,Wohlfart P,Langer T,Müller CW,Dreyer MK,Lawrence MCdoi
10.1038/s41467-018-06826-6subject
Has Abstractpub_date
2018-10-24 00:00:00pages
4420issue
1issn
2041-1723pii
10.1038/s41467-018-06826-6journal_volume
9pub_type
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