9vay
Cryo-EM structure of human Neurotensin Receptor 1 (hNTSR1)-Gi1 complex in nucleotide-free C state 2
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedG-protein-coupled receptor (GPCR) signalling occurs through heterotrimeric G proteins, whose selective activation leads to distinct cellular outcomes(1). Although more than 200 GPCR-G protein complex structures have been determined(2), these static snapshots provide limited insight into the dynamics of G-protein association and dissociation. Here we present cryo-electron microscopy structures of human neurotensin receptor type 1 (NTSR1) with minimally modified G(o) and G(q), showing how the receptor's intracellular surface dynamically rearranges to accommodate each G-protein subtype. Furthermore, time-resolved cryo-electron microscopy analyses of NTSR1-G(i) visualized G-protein dissociation processes on GDP/GTP binding. Characterization of more than 20 intermediates, complemented by mutational and computational analyses, identifies four key mechanistic features. First, GDP/GTP induces G(i) release from both canonical and non-canonical active conformations with distinct kinetics. Second, NTSR1 uses common intracellular rearrangements to recognize different G-protein subtypes and to promote activation of a single subtype. Third, separation from Gbetagamma involves stepwise remodelling of the Galpha switches I-III. Finally, G(i) dissociates from the receptor through a pathway that is distinct from that of G(s), and the canonical and non-canonical NTSR1-G(i) complexes further diverge in their dissociation trajectories. These findings provide a comprehensive framework for understanding GPCR signalling dynamics and guiding signal-targeted therapeutic development. The dynamic basis of G-protein recognition and activation by a GPCR.,Kobayashi K, Kawakami K, Matsui TE, Yokoi S, Fukuda M, Narita TJ, Arai H, Tambo M, Sumikama T, Tatsumi M, Yamashita K, Koyanagi J, Kugawa M, Ikeda H, Sumino A, Mitsutake A, Kobilka BK, Inoue A, Kato HE Nature. 2026 Apr;652(8110):812-821. doi: 10.1038/s41586-026-10228-w. Epub 2026 , Mar 11. PMID:41813902[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
