7U6D

Head region of insulin receptor ectodomain (A-isoform) bound to the non-insulin agonist IM459

7U6D の概要

• エントリーDOI: 10.2210/pdb7u6d/pdb
• EMDBエントリー: 26363 26364
• 分子名称: IM459, Isoform Short of Insulin receptor (2 entities in total)
• 機能のキーワード: insulin receptor, insulin-mimic peptide, insulin receptor agonist, signaling protein-agonist complex, signaling protein/agonist
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 213215.92

構造登録者

Kirk, N.S.,Lawrence, M.C. (登録日: 2022-03-03, 公開日: 2022-10-05, 最終更新日: 2025-05-28)

主引用文献

Kirk, N.S.,Chen, Q.,Wu, Y.G.,Asante, A.L.,Hu, H.,Espinosa, J.F.,Martinez-Olid, F.,Margetts, M.B.,Mohammed, F.A.,Kiselyov, V.V.,Barrett, D.G.,Lawrence, M.C.
Activation of the human insulin receptor by non-insulin-related peptides
Nat Commun, 13:5695-, 2022

PubMed Abstract: 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.

PubMed: 36171189
DOI: 10.1038/s41467-022-33315-8

実験手法

ELECTRON MICROSCOPY (5.03 Å)