Neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple subtypes of G protein, and is involved in the regulation of blood pressure, body temperature, weight and the response to pain. Here we present structures of human NTSR1 in complex with the agonist JMV449 and the heterotrimeric G_i1 protein, at a resolution of 3 Å. We identify two conformations: a canonical-state complex that is similar to recently reported GPCR–G_i/o complexes (in which the nucleotide-binding pocket adopts more flexible conformations that may facilitate nucleotide exchange), and a non-canonical state in which the G protein is rotated by about 45 degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. In the non-canonical state, NTSR1 exhibits features of both active and inactive conformations, which suggests that the structure may represent an intermediate form along the activation pathway of G proteins. This structural information, complemented by molecular dynamics simulations and functional studies, provides insights into the complex process of G-protein activation.

In addition to the serotonin 5-HT_2A receptor (5-HT_2AR), the dopamine D₂ receptor (D₂R) is a key therapeutic target of antipsychotics for the treatment of schizophrenia. The inactive state structures of D₂R have been described in complex with the inverse agonists risperidone (D₂R_ris) and haloperidol (D₂R_hal). Here we describe the structure of human D₂R in complex with spiperone (D₂R_spi). In D₂R_spi, the conformation of the extracellular loop (ECL) 2, which composes the ligand-binding pocket, was substantially different from those in D₂R_ris and D₂R_hal, demonstrating that ECL2 in D₂R is highly dynamic. Moreover, D₂R_spi exhibited an extended binding pocket to accommodate spiperone’s phenyl ring, which probably contributes to the selectivity of spiperone to D₂R and 5-HT_2AR. Together with D₂R_ris and D₂R_hal, the structural information of D₂R_spi should be of value for designing novel antipsychotics with improved safety and efficacy.

Endothelin receptors (ET _A and ET _B ) are class A GPCRs activated by vasoactive peptide endothelins, and are involved in blood pressure regulation. ET _B -selective signalling induces vasorelaxation, and thus selective ET _B agonists are expected to be utilized for improved anti-tumour drug delivery and neuroprotection. Here, we report the crystal structures of human ET _B receptor in complex with ET _B -selective agonist, endothelin-3 and an ET _B -selective endothelin analogue IRL1620. The structure of the endothelin-3-bound receptor reveals that the disruption of water-mediated interactions between W6.48 and D2.50 is critical for receptor activation, while these hydrogen-bonding interactions are partially preserved in the IRL1620-bound structure. Consistently, functional analysis reveals the partial agonistic effect of IRL1620. The current findings clarify the detailed molecular mechanism for the coupling between the orthosteric pocket and the G-protein binding, and the partial agonistic effect of IRL1620, thus paving the way for the design of improved agonistic drugs targeting ET _B .