7MQS

The insulin receptor ectodomain in complex with three venom hybrid insulin molecules - asymmetric conformation

7MQS の概要

• エントリーDOI: 10.2210/pdb7mqs/pdb
• 関連するPDBエントリー: 7MQO 7MQR
• EMDBエントリー: 23951
• 分子名称: Isoform Short of Insulin receptor, Insulin A chain, Insulin B chain (3 entities in total)
• 機能のキーワード: insulin, receptor, venom, cone snail, hormone, toxin
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 225087.56

構造登録者

Blakely, A.D.,Xiong, X.,Kim, J.H.,Menting, J.,Schafer, I.B.,Schubert, H.L.,Agrawal, R.,Gutmann, T.,Delaine, C.,Zhang, Y.,Artik, G.O.,Merriman, A.,Eckert, D.,Lawrence, M.C.,Coskun, U.,Fisher, S.J.,Forbes, B.E.,Safavi-Hemami, H.,Hill, C.P.,Chou, D.H.C. (登録日: 2021-05-06, 公開日: 2022-03-16, 最終更新日: 2024-10-23)

主引用文献

Xiong, X.,Blakely, A.,Kim, J.H.,Menting, J.G.,Schafer, I.B.,Schubert, H.L.,Agrawal, R.,Gutmann, T.,Delaine, C.,Zhang, Y.W.,Artik, G.O.,Merriman, A.,Eckert, D.,Lawrence, M.C.,Coskun, U.,Fisher, S.J.,Forbes, B.E.,Safavi-Hemami, H.,Hill, C.P.,Chou, D.H.
Symmetric and asymmetric receptor conformation continuum induced by a new insulin.
Nat.Chem.Biol., 18:511-519, 2022

PubMed Abstract: Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes and biochemical properties. Here, we report an active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy (cryo-EM) and protein engineering to elucidate its interactions with the human insulin receptor (IR) ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of human insulin but also compromise therapeutic utility by delaying dissolution from the site of subcutaneous injection. This finding suggests approaches to developing improved therapeutic insulins. Curiously, the receptor displays a continuum of conformations from the symmetric state to a highly asymmetric low-abundance structure that displays coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions.

PubMed: 35289328
DOI: 10.1038/s41589-022-00981-0

実験手法

ELECTRON MICROSCOPY (4.4 Å)