8THK

Cryo-EM structure of A61603-bound alpha-1A-adrenergic receptor in complex with heterotrimeric Gq-protein

8THK の概要

• エントリーDOI: 10.2210/pdb8thk/pdb
• EMDBエントリー: 41267
• 分子名称: Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short,Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• 機能のキーワード: alpha-1a-adrenergic receptor, a61603, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 160827.61

構造登録者

Su, M.,Huang, X.Y. (登録日: 2023-07-17, 公開日: 2023-08-16, 最終更新日: 2024-11-06)

主引用文献

Su, M.,Wang, J.,Xiang, G.,Do, H.N.,Levitz, J.,Miao, Y.,Huang, X.Y.
Structural basis of agonist specificity of alpha 1A -adrenergic receptor.
Nat Commun, 14:4819-4819, 2023

PubMed Abstract: α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α subtypes has limited our understanding of the physiological roles of different α-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α-AR and α-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α-AR mutants that are not responsive to A61603, and α-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.

PubMed: 37563160
DOI: 10.1038/s41467-023-40524-2

実験手法

ELECTRON MICROSCOPY (2.6 Å)