Structure of neurotensin receptor NTS1
 |
Figure: Overview of the NTS1
structure bound to the peptide agonist NT8-13. Cartoon
representation of NTS1 in side view. NTS1 is shown in green and T4 lysozyme
used to promote crystal contacts is in brown. Space filling models are used
to depict the agonist NTS8-13 (orange), the side chains of
thermostabilizing mutations (purple) and the disulphide bond (yellow) between
the conserved residues C142 and C225. Also shown are the beta-hairpin in
extracellular loop 2 (blue-green) and the pi-helix in intracellular loop 2
(ICL2). |
Reinhard Grisshammer group (The National Institutes of Health) and collaborators
Reinhard Grisshammer's group at the NIH determined the
structure of the agonist-bound neurotensin receptor NTS1, which is the first
structure of a G protein-coupled receptor (GPCR) with a bound peptide.
Neurotensin (NT) is a 13 amino acid peptide that functions as both a
neurotransmitter and as a hormone through activation of the neurotensin
receptor NTS1, a GPCR that signals preferentially through Gq. In the brain,
NT modulates activity of dopaminergic systems, opioid-independent analgesia,
and the inhibition of food intake, and in the gut NT regulates a range of
digestive processes. The researchers reported a 2.8-Å structure of
NTS1 in an active-like state, bound to NT8-13, the C terminal
portion of NT responsible for agonist-induced activation of the receptor.
Because wild-type NTS1 is unstable and thus not amenable to crystallization,
they used alanine-scanning mutagenesis to stabilize NTS1 and to select for an
active-like conformation in the presence of agonist, which combined with the
bacteriophage T4 lysozyme fusion protein strategy and the lipidic mesophase
crystallization method, resulted in diffracting crystals. The agonist binding
pocket is located at the extracellular receptor surface. The peptide agonist
binds to NTS1 in an extended conformation nearly perpendicular to the
membrane plane with the C-terminus oriented towards the receptor core. The
NTS1 structure bears many hallmark features of an active-like receptor
conformation such as an outward-tilted transmembrane helix 6 at the
cytoplasmic surface and key conserved residues in positions characteristic of
active but not inactive GPCRs.
Citation:
White, JF, Noinaj, N, Shibata, Y, Love, J, Kloss, B, Xu, F,
Gvozdenovic-Jeremic, J, Shah, P, Shiloach, J, Tate, CG, Grisshammer, R.
Structure of the agonist-bound neurotensin receptor, Nature 490, 508-513
(2012). DOI: 10.1038/nature11558
|
