Activation of the human insulin receptor by non-insulin-related peptides.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 09 2022
28 09 2022
Historique:
received:
21
04
2022
accepted:
12
09
2022
entrez:
28
9
2022
pubmed:
29
9
2022
medline:
1
10
2022
Statut:
epublish
Résumé
The human insulin receptor signalling system plays a critical role in glucose homeostasis. Insulin binding brings about extensive conformational change in the receptor extracellular region that in turn effects trans-activation of the intracellular tyrosine kinase domains and downstream signalling. Of particular therapeutic interest is whether insulin receptor signalling can be replicated by molecules other than insulin. Here, we present single-particle cryoEM structures that show how a 33-mer polypeptide unrelated to insulin can cross-link two sites on the receptor surface and direct the receptor into a signalling-active conformation. The 33-mer polypeptide engages the receptor by two helical binding motifs that are each potentially mimicable by small molecules. The resultant conformation of the receptor is distinct from-but related to-those in extant three-dimensional structures of the insulin-complexed receptor. Our findings thus illuminate unexplored pathways for controlling the signalling of the insulin receptor as well as opportunities for development of insulin mimetics.
Identifiants
pubmed: 36171189
doi: 10.1038/s41467-022-33315-8
pii: 10.1038/s41467-022-33315-8
pmc: PMC9519552
doi:
Substances chimiques
Insulin
0
Receptor, Insulin
EC 2.7.10.1
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5695Informations de copyright
© 2022. The Author(s).
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