Structural prerequisites for G-protein activation by the neurotensin receptor

Krumm, Brian E.; White, Jim F.; Shah, Priyanka; Grisshammer, Reinhard

doi:10.1038/ncomms8895

Structural prerequisites for G-protein activation by the neurotensin receptor

Journal Article · Fri Jul 24 00:00:00 EDT 2015 · Nature Communications

DOI:https://doi.org/10.1038/ncomms8895· OSTI ID:1203746

Krumm, Brian E. ^[1]; White, Jim F. ^[1]; Shah, Priyanka ^[1]; Grisshammer, Reinhard ^[1]

National Inst. of Health (NIH), Rockville, MD (United States). Dept. of Health and Human Services

We previously determined the structure of neurotensin receptor NTSR1 in an active-like conformation with six thermostabilizing mutations bound to the peptide agonist neurotensin. This receptor was unable to activate G proteins, indicating that the mutations restricted NTSR1 to relate agonist binding to G-protein activation. Here we analyse the effect of three of those mutations (E166A^3.49, L310A^6.37, F358A^7.42) and present two structures of NTSR1 able to catalyse nucleotide exchange at Gα. The presence of F358^7.42 causes the conserved W321^6.48 to adopt a side chain orientation parallel to the lipid bilayer sealing the collapsed Na+ ion pocket and linking the agonist with residues in the lower receptor part implicated in GPCR activation. In the intracellular receptor half, the bulkier L310^6.37 side chain dictates the position of R167^3.50 of the highly conserved D/ERY motif. These residues, together with the presence of E166^3.49 provide determinants for G-protein activation by NTSR1.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: NIH; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357; AC02-76SF00515

OSTI ID:: 1203746

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 07, 2015 Vol. 6; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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