Structure of the agonist-bound neurotensin receptor

Article

关键词: PROTEIN-COUPLED RECEPTOR;    CRYSTAL-STRUCTURE;    MEMBRANE-PROTEINS;    OPIOID RECEPTOR;    BINDING-SITE;    ACTIVE STATE;    PEPTIDE;    GPCR;    ACTIVATION;    INSIGHTS;   

DOI  :  10.1038/nature11558

来源: SCIE

【 摘 要 】

Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 angstrom resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS8-13, the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.

【 授权许可】

Free