9P8A

NTSR1-G11-NTS(8-13) GTP-Bound Complex in the Canonical, AHD Closed State 3DVA Separated 2 (C-Closed*-GTP)

9P8A の概要

• エントリーDOI: 10.2210/pdb9p8a/pdb
• EMDBエントリー: 71370
• 分子名称: Guanine nucleotide-binding protein subunit alpha-11, 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: complex, agonist, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 88232.68

構造登録者

Robertson, M.J. (登録日: 2025-06-22, 公開日: 2026-03-25)

主引用文献

Vo, A.A.,Modak, A.,Lu, S.,Blanchard, S.C.,Lambert, N.A.,Robertson, M.J.
Snapshots of the dynamic basis of NTSR1 G protein subtype promiscuity.
Nature, 2026

PubMed Abstract: G-protein-coupled receptors (GPCRs) are capable of signalling through four families of G protein α subunits. Although hundreds of nucleotide-free GPCR-G protein complex structures have been solved, the mechanism of G protein subtype selectivity remains poorly understood, with recent studies suggesting a role for dynamic nucleotide-bound intermediate states. Here we use time-resolved cryo-electron microscopy to visualize the GTP-induced activation of Gαβγ and Gαβγ heterotrimers bound to the neurotensin receptor 1 (NTSR1), which has been demonstrated to be highly promiscuous in G protein coupling and to possess unusual conformations in the nucleotide-free complex. We resolve ensembles of states along the G protein activation pathway, with differences in the structures and their relative populations between Gα and Gα. Structural analysis reveals a key role for several motifs, including intracellular loop 2 (ICL2) and ICL3, in stabilizing the observed intermediate states. Our results are supported by molecular dynamics simulations and kinetic bioluminescence resonance energy transfer experiments, which reveal that the stability of these intermediate states and the signalling of various G proteins are correlated with ICL2 and ICL3 sequences. Single-molecule fluorescence assays of GTP-induced NTSR1-G protein complex dissociation reveal that NTSR1 is liberated significantly faster from Gα, consistent with the relative lack of stable Gα-GTP intermediate states compared with Gα. These findings highlight that transient intermediate-state complexes along the G protein activation pathway have an important role in G protein selection that cannot be explained by nucleotide-free states alone.

PubMed: 41813894
DOI: 10.1038/s41586-026-10120-7

実験手法

ELECTRON MICROSCOPY (3.7 Å)