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-Structure paper
タイトル | Activation of the human insulin receptor by non-insulin-related peptides. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 5695, Year 2022 |
掲載日 | 2022年9月28日 |
著者 | Nicholas 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 要旨 | 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 ...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. |
リンク | Nat Commun / PubMed:36171189 / PubMed Central |
手法 | EM (単粒子) / NMR (溶液) |
解像度 | 3.0 - 5.03 Å |
構造データ | EMDB-26363, PDB-7u6d: EMDB-26364, PDB-7u6e: PDB-8di2: |
化合物 | ChemComp-NAG: |
由来 |
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キーワード | SIGNALING PROTEIN/AGONIST / insulin receptor (インスリン受容体) / insulin-mimic peptide / insulin receptor agonist / SIGNALING PROTEIN-AGONIST complex / HORMONE/SIGNALING PROTEIN/AGONIST / HORMONE-SIGNALING PROTEIN-AGONIST complex / SIGNALING PROTEIN / Receptor / tyrosine kinase (プロテインチロシンキナーゼ) |