The conformation of neurotensin bound to its G protein-coupled receptor

Sorin M Luca, Jim F. White, Awinder K. Sohal, Dmitri V. Filippov, Jacques H. Van Boom, Reinhard Grisshammer, Marc Baldus

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Abstract

G protein-coupled receptors (GPCRs) mediate the perception of smell, light, taste, and pain. They are involved in signal recognition and cell communication and are some of the most important targets for drug development. Because currently no direct structural information on high-affinity ligands bound to GPCRs is available, rational drug design is limited to computational prediction combined with mutagenesis experiments. Here, we present the conformation of a high-affinity peptide agonist (neurotensin, NT) bound to its GPCR NTS-1, determined by direct structural methods. Functional receptors were expressed in Escherichia coli, purified in milligram amounts by using optimized procedures, and subsequently reconstituted into lipid vesicles. Solid-state NMR experiments were tailored to allow for the unequivocal detection of microgram quantities of 13C,15N-labeled NT(8-13) in complex with functional NTS-1. The NMR data are consistent with a disordered state of the ligand in the absence of receptor. Upon receptor binding, the peptide undergoes a linear rearrangement, adopting a β-strand conformation. Our results provide a viable structural template for further pharmacological investigations.

Original languageEnglish (US)
Pages (from-to)10706-10711
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number19
DOIs
StatePublished - Sep 16 2003

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Neurotensin
G-Protein-Coupled Receptors
neurotensin (8-13)
Ligands
Peptides
Smell
Drug Design
Cell Communication
Mutagenesis
Pharmacology
Escherichia coli
Lipids
Light
Pain
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

Cite this

Luca, S. M., White, J. F., Sohal, A. K., Filippov, D. V., Van Boom, J. H., Grisshammer, R., & Baldus, M. (2003). The conformation of neurotensin bound to its G protein-coupled receptor. Proceedings of the National Academy of Sciences of the United States of America, 100(19), 10706-10711. https://doi.org/10.1073/pnas.1834523100

The conformation of neurotensin bound to its G protein-coupled receptor. / Luca, Sorin M; White, Jim F.; Sohal, Awinder K.; Filippov, Dmitri V.; Van Boom, Jacques H.; Grisshammer, Reinhard; Baldus, Marc.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 19, 16.09.2003, p. 10706-10711.

Research output: Contribution to journalArticle

Luca, SM, White, JF, Sohal, AK, Filippov, DV, Van Boom, JH, Grisshammer, R & Baldus, M 2003, 'The conformation of neurotensin bound to its G protein-coupled receptor', Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 19, pp. 10706-10711. https://doi.org/10.1073/pnas.1834523100
Luca, Sorin M ; White, Jim F. ; Sohal, Awinder K. ; Filippov, Dmitri V. ; Van Boom, Jacques H. ; Grisshammer, Reinhard ; Baldus, Marc. / The conformation of neurotensin bound to its G protein-coupled receptor. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 19. pp. 10706-10711.
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