9EEA

Cryo-EM structure of the adenosine A2A receptor intermediate bound to a miniGs heterotrimer

9EEA の概要

• エントリーDOI: 10.2210/pdb9eea/pdb
• EMDBエントリー: 47953
• 分子名称: Adenosine receptor A2a, 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: gpcr, heterotrimer, receptor, cryo-em, 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: 5
• 化学式量合計: 133076.40

構造登録者

Bi, M.,Wang, X.,Ye, L.,Cheng, Y. (登録日: 2024-11-18, 公開日: 2025-04-09, 最終更新日: 2025-08-13)

主引用文献

Bi, M.,Wang, X.,Wang, J.,Xu, J.,Sun, W.,Adediwura, V.A.,Miao, Y.,Cheng, Y.,Ye, L.
Structure and function of a near fully-activated intermediate GPCR-G alpha beta gamma complex.
Nat Commun, 16:1100-1100, 2025

PubMed Abstract: Unraveling the signaling roles of intermediate complexes is pivotal for G protein-coupled receptor (GPCR) drug development. Despite hundreds of GPCR-Gαβγ structures, these snapshots primarily capture the fully activated complex. Consequently, the functions of intermediate GPCR-G protein complexes remain elusive. Guided by a conformational landscape visualized via F quantitative NMR and molecular dynamics (MD) simulations, we determined the structure of an intermediate GPCR-mini-Gαβγ complex at 2.6 Å using cryo-EM, by blocking its transition to the fully activated complex. Furthermore, we present direct evidence that the complex at this intermediate state initiates a rate-limited nucleotide exchange before transitioning to the fully activated complex. In this state, BODIPY-GDP/GTP based nucleotide exchange assays further indicated the α-helical domain of the Gα is partially open, allowing it to grasp a nucleotide at a non-canonical binding site, distinct from the canonical nucleotide-binding site. These advances bridge a significant gap in our understanding of the complexity of GPCR signaling.

PubMed: 39875358
DOI: 10.1038/s41467-025-56434-4

実験手法

ELECTRON MICROSCOPY (3.36 Å)