8DCS

Cryo-EM structure of cyanopindolol-bound beta1-adrenergic receptor in complex with heterotrimeric Gs-protein

8DCS の概要

• エントリーDOI: 10.2210/pdb8dcs/pdb
• EMDBエントリー: 27329
• 分子名称: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Nanobody 35, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, ... (6 entities in total)
• 機能のキーワード: beta1-adrenergic receptor, cyanopindolol, partial agonist, signaling protein
• 由来する生物種: Bos taurus (cattle); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 163354.28

構造登録者

Su, M.,Paknejad, N.,Hite, R.K.,Huang, X.Y. (登録日: 2022-06-17, 公開日: 2022-07-27, 最終更新日: 2025-07-23)

主引用文献

Su, M.,Paknejad, N.,Zhu, L.,Wang, J.,Do, H.N.,Miao, Y.,Liu, W.,Hite, R.K.,Huang, X.Y.
Structures of beta 1 -adrenergic receptor in complex with Gs and ligands of different efficacies.
Nat Commun, 13:4095-4095, 2022

PubMed Abstract: G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies, and transduce to heterotrimeric G-proteins to generate different degrees of physiological responses. Previous studies revealed how ligands with different efficacies activate GPCRs. Here, we investigate how a GPCR activates G-proteins upon binding ligands with different efficacies. We report the cryo-EM structures of β-adrenergic receptor (β-AR) in complex with Gs (GαGβGγ) and a partial agonist or a very weak partial agonist, and compare them to the β-AR-Gs structure in complex with a full agonist. Analyses reveal similar overall complex architecture, with local conformational differences. Cellular functional studies with mutations of β-AR residues show effects on the cellular signaling from β-AR to the cAMP response initiated by the three different ligands, with residue-specific functional differences. Biochemical investigations uncover that the intermediate state complex comprising β-AR and nucleotide-free Gs is more stable when binding a full agonist than a partial agonist. Molecular dynamics simulations support the local conformational flexibilities and different stabilities among the three complexes. These data provide insights into the ligand efficacy in the activation of GPCRs and G-proteins.

PubMed: 35835792
DOI: 10.1038/s41467-022-31823-1

実験手法

ELECTRON MICROSCOPY (2.5 Å)