9CBM

Cryo-EM structure of dexmedetomidine-bound alpha-2A-adrenergic receptor in complex with heterotrimeric Gi-protein

9CBM の概要

• エントリーDOI: 10.2210/pdb9cbm/pdb
• EMDBエントリー: 45426
• 分子名称: Guanine nucleotide-binding protein G(i) subunit alpha-1, 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, ... (5 entities in total)
• 機能のキーワード: gpcr adrenergic receptor, signaling protein
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 143194.03

構造登録者

Lou, J.S.,Su, M.,Wang, J.,Do, H.N.,Miao, Y.,Huang, X.Y. (登録日: 2024-06-19, 公開日: 2024-09-11, 最終更新日: 2024-10-16)

主引用文献

Lou, J.S.,Su, M.,Wang, J.,Do, H.N.,Miao, Y.,Huang, X.Y.
Distinct binding conformations of epinephrine with alpha- and beta-adrenergic receptors.
Exp.Mol.Med., 56:1952-1966, 2024

PubMed Abstract: Agonists targeting α-adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, attention-deficit/hyperactivity disorder, pain, panic disorders, opioid and alcohol withdrawal symptoms, and cigarette cravings. These receptors transduce signals through heterotrimeric Gi proteins. Here, we elucidated cryo-EM structures that depict α-AR in complex with Gi proteins, along with the endogenous agonist epinephrine or the synthetic agonist dexmedetomidine. Molecular dynamics simulations and functional studies reinforce the results of the structural revelations. Our investigation revealed that epinephrine exhibits different conformations when engaging with α-ARs and β-ARs. Furthermore, α-AR and β-AR (primarily coupled to Gs, with secondary associations to Gi) were compared and found to exhibit different interactions with Gi proteins. Notably, the stability of the epinephrine-α-AR-Gi complex is greater than that of the dexmedetomidine-α-AR-Gi complex. These findings substantiate and improve our knowledge on the intricate signaling mechanisms orchestrated by ARs and concurrently shed light on the regulation of α-ARs and β-ARs by epinephrine.

PubMed: 39218975
DOI: 10.1038/s12276-024-01296-x

実験手法

ELECTRON MICROSCOPY (3.2 Å)