Structure of the agonist-bound neurotensin receptor.
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 Å resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), 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.
Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland 20852, USA.
Jim F
JF
White
Nicholas
N
Noinaj
Yoko
Y
Shibata
James
J
Love
Brian
B
Kloss
Feng
F
Xu
Jelena
J
Gvozdenovic-Jeremic
Priyanka
P
Shah
Joseph
J
Shiloach
Christopher G
CG
Tate
Reinhard
R
Grisshammer
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D017122:Bacteriophage T4; D001665:Binding Sites; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D009113:Muramidase; D009154:Mutation; D009496:Neurotensin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats; D018028:Receptors, Neurotensin / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D018028:Receptors, Neurotensin; D009496:Neurotensin; D009113:Muramidase