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TitleActivation of the human insulin receptor by non-insulin-related peptides.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 5695, Year 2022
Publish dateSep 28, 2022
AuthorsNicholas S Kirk / Qi Chen / Yingzhe Ginger Wu / Anastasia L Asante / Haitao Hu / Juan F Espinosa / Francisco Martínez-Olid / Mai B Margetts / Faiz A Mohammed / Vladislav V Kiselyov / David G Barrett / Michael C Lawrence /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:36171189 / PubMed Central
MethodsEM (single particle) / NMR (solution)
Resolution3.0 - 5.03 Å
Structure data

26363

7u6d

EMDB-26363, PDB-7u6d:
Head region of insulin receptor ectodomain (A-isoform) bound to the non-insulin agonist IM459
Method: EM (single particle) / Resolution: 5.03 Å

26364

7u6e

EMDB-26364, PDB-7u6e:
Head region of insulin receptor ectodomain (A-isoform) bound to the non-insulin agonist IM462
Method: EM (single particle) / Resolution: 3.0 Å

PDB-8di2:
Site 2 insulin receptor binding peptide IM459N21
Method: SOLUTION NMR

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsSIGNALING PROTEIN/AGONIST / insulin receptor / insulin-mimic peptide / insulin receptor agonist / SIGNALING PROTEIN-AGONIST complex / HORMONE/SIGNALING PROTEIN/AGONIST / HORMONE-SIGNALING PROTEIN-AGONIST complex / SIGNALING PROTEIN / Receptor / tyrosine kinase

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