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G protein-coupled receptors

Pioneering peptide GPCR structure determined

Nature Reviews Drug Discovery volume 11, page 832 (2012)Cite this article

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Wild-type NTSR1 is unstable in detergent solution, and so conformational thermostabilization through the introduction of amino acid mutations at six locations was used to produce crystals of rat mutant NTSR1 (termed NTSR1-GW5) in the presence of the carboxy-terminal portion of NTS (NTS8–13). NTSR1-GW5 then had T4 lysozyme (T4L) engineered into intracellular loop 3 (ICL3) to improve the likelihood of obtaining well-diffracting crystals. NTSR1-GW5-T4L was expressed in insect cells, solubilized and then crystallized using the lipidic cubic phase methodology. The structure was determined at a resolution of 2.8 Å using molecular replacement.

The overall structure of NTSR1-GW5-T4L is similar to other GPCR structures determined so far, except that it has no helix 8, which has been observed in all GPCR structures apart from CXC chemokine receptor 4. This may be because NTSR1-GW5-T4L does not have this helix or because of an artefact of the crystallization procedure. Moreover, transmembrane helix 7 (TM7) extends by three helical turns beyond the conserved NPXXY motif, in contrast to other GPCRs, which extend only by one turn.

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ORIGINAL RESEARCH PAPER

  1. White, J. F. et al. Structure of the agonist-bound neurotensin receptor. Nature 490, 508–513 (2012)

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  1. Man Tsuey Tse
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Tse, M. Pioneering peptide GPCR structure determined. Nat Rev Drug Discov 11, 832 (2012). https://doi.org/10.1038/nrd3875

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