8F2A

Human Amylin3 Receptor in complex with Gs and Pramlintide analogue peptide San385 (Cluster 5 conformation)

8F2A の概要

• エントリーDOI: 10.2210/pdb8f2a/pdb
• 関連するPDBエントリー: 8F0K
• EMDBエントリー: 28810
• 分子名称: Receptor activity-modifying protein 3, Pramlintide analogue San385, Calcitonin receptor, ... (8 entities in total)
• 機能のキーワード: gpcr, amylin receptor, receptor activity-modifying protein, signaling protein-immune system complex, signaling protein/immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 7
• 化学式量合計: 187465.98

構造登録者

Cao, J.,Sexton, P.M.,Wootten, D.L.,Radostin, D. (登録日: 2022-11-07, 公開日: 2023-08-02, 最終更新日: 2024-10-30)

主引用文献

Cao, J.,Belousoff, M.J.,Gerrard, E.,Danev, R.,Fletcher, M.M.,Dal Maso, E.,Schreuder, H.,Lorenz, K.,Evers, A.,Tiwari, G.,Besenius, M.,Li, Z.,Johnson, R.M.,Wootten, D.,Sexton, P.M.
Structural insight into selectivity of amylin and calcitonin receptor agonists.
Nat.Chem.Biol., 20:162-169, 2024

PubMed Abstract: Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formation of a 'bypass' secondary structural motif (residues S19-P25). This study explored potential tuning of peptide selectivity through modification to residues 19-22, resulting in a selective AMYR agonist, San385, as well as nonselective dual amylin and calcitonin receptor agonists (DACRAs), with San45 being an exemplar. We determined the structure and dynamics of San385-bound AMYR, and San45 bound to AMYR or CTR. San45, via its conjugated lipid at position 21, was anchored at the edge of the receptor bundle, enabling a stable, alternative binding mode when bound to the CTR, in addition to the bypass mode of binding to AMYR. Targeted lipid modification may provide a single intervention strategy for design of long-acting, nonselective, Amy-based DACRAs with potential anti-obesity effects.

PubMed: 37537379
DOI: 10.1038/s41589-023-01393-4

実験手法

ELECTRON MICROSCOPY (2.2 Å)