Conformational transitions of a neurotensin receptor 1–G(i1) protein complex

The neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple G-protein subtypes and is involved in regulation of blood pressure, body temperature, weight, and response to pain. Here we present 3-Å structures of the human NTSR1 in complex with the agonist JMV449 and the heterotrimeric G(i1) protein in two conformations (C state and NC state). While the C-state complex is similar to recently reported GPCR-G(i/o) complexes, with the nucleotide-binding pocket adopting more flexible conformations that may facilitate nucleotide exchange, the G protein in the NC state is rotated by ~45 degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. NTSR1 in the NC state exhibits features of both active and inactive conformations, suggesting that the structure may represent an intermediate along the G-protein-activation pathway. This structural information, complemented by molecular dynamics simulations and functional studies, provides insights into the complex process of G-protein activation.