Snapshots of the dynamic basis of NTSR1 G protein subtype promiscuity - PubMed
14 hours ago
- #G protein activation
- #cryo-EM
- #GPCR
- The study uses time-resolved cryo-electron microscopy to explore GTP-induced activation of Gαi1βγ and Gα11βγ heterotrimers bound to neurotensin receptor 1 (NTSR1).
- NTSR1 is highly promiscuous in G protein coupling and exhibits unusual conformations in nucleotide-free complexes.
- Structural analysis identifies intracellular loop 2 (ICL2) and ICL3 as key in stabilizing intermediate states during G protein activation.
- Molecular dynamics simulations and kinetic bioluminescence resonance energy transfer experiments support the findings, linking intermediate state stability to G protein signaling.
- Single-molecule fluorescence assays show NTSR1 is liberated faster from Gα11 than Gαi1, correlating with fewer stable Gα11-GTP intermediate states.
- The study highlights the importance of transient intermediate-state complexes in G protein selection, beyond nucleotide-free states.