TY - JOUR
T1 - Structure of the agonist-bound neurotensin receptor
AU - White, Jim F.
AU - Noinaj, Nicholas
AU - Shibata, Yoko
AU - Love, James
AU - Kloss, Brian
AU - Xu, Feng
AU - Gvozdenovic-Jeremic, Jelena
AU - Shah, Priyanka
AU - Shiloach, Joseph
AU - Tate, Christopher G.
AU - Grisshammer, Reinhard
N1 - Funding Information:
Acknowledgements This research was supported by the Intramural Research Program of the National Institutes of Health (J.F.W., J.G.-J., P.S. and R.G.: National Institute of Neurological Disorders and Stroke; N.N. and J.S.: National Institute of Diabetes and Digestive and Kidney Diseases) and a joint grant from Pfizer Global Research and Development and the MRCT Development Gap Fund in addition to core funding from the UK Medical Research Council MRC U105197215 (Y.S., C.G.T.). The Protein Production Facility of the New York Consortium on Membrane Protein Structure was supported by the National Institutes of Health grant U54GM075026 (J.L., B.K.). We acknowledge the NIH Roadmap grant P50 GM073197 for technology development (to R. C. Stevens) for visitor support at The Scripps Research Institute. We thank the staff at the General Medicine and Cancer Institute’s Collaborative Access Team (GM/CA-CAT) beamline at the Advanced Photon Source, Argonne National Laboratory for their assistance during data collection. Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract No. DE-AC02-06CH11357.
PY - 2012/10/25
Y1 - 2012/10/25
N2 - 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 2.8Å 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.
AB - 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 2.8Å 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.
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U2 - 10.1038/nature11558
DO - 10.1038/nature11558
M3 - Article
C2 - 23051748
AN - SCOPUS:84867840947
SN - 0028-0836
VL - 490
SP - 508
EP - 513
JO - Nature
JF - Nature
IS - 7421
ER -