Publication Date:
2012-10-12
Description:
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 A 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482300/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482300/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉White, Jim F -- Noinaj, Nicholas -- Shibata, Yoko -- Love, James -- Kloss, Brian -- Xu, Feng -- Gvozdenovic-Jeremic, Jelena -- Shah, Priyanka -- Shiloach, Joseph -- Tate, Christopher G -- Grisshammer, Reinhard -- MC_U105197215/Medical Research Council/United Kingdom -- P50 GM073197/GM/NIGMS NIH HHS/ -- U105197215/Medical Research Council/United Kingdom -- U54GM075026/GM/NIGMS NIH HHS/ -- ZIA NS003016-05/Intramural NIH HHS/ -- England -- Nature. 2012 Oct 25;490(7421):508-13. doi: 10.1038/nature11558. Epub 2012 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23051748" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Motifs
;
Amino Acid Sequence
;
Animals
;
Bacteriophage T4
;
Binding Sites
;
Crystallography, X-Ray
;
Models, Molecular
;
Muramidase
;
Mutation
;
Neurotensin/chemistry/genetics/*metabolism
;
Protein Conformation
;
Rats
;
Receptors, Neurotensin/*agonists/*chemistry/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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