Feeling at home: Structure of the NTSR1–Gi complex in a lipid environment

Abstract

The interaction of G protein-coupled receptors (GPCRs) with heterotrimeric G proteins plays a critical role in signal transduction processes, and multiple GPCR-G protein complexes reconstituted in detergent micelles have been visualized using cryo-EM. A new study reports the structure of neurotensin receptor 1 (NTSR1) in complex with the heterotrimeric G i protein, assembled in a lipid environment using circularized nanodiscs. The structure sheds light on how the lipid context may influence receptor-G protein coupling and activation.GPCRS constitute a large family of cell surface proteins in the human genome, with more than 800 members, and they continue to be one of the most sought-after drug targets for a range of human disorders 1 . They exhibit incredible diversity in their ligand-recognition ability on the extracellular side but converge significantly on the transducers they are coupled with on the intracellular side. Agonist-induced activation of heterotrimeric G proteins associated with GPCRs is responsible for a broad spectrum of cellular signaling pathways involved in diverse physiological processes. The technological advance in cryo-EM has clearly revolutionized our understanding of the structural basis of GPCR activation and signaling, and the structural coverage of GPCR-G protein complexes continues to grow at a staggering pace 2 . This has resulted in cryo-EM structures of GPCRs from different subfamilies in complex with different G protein sub-types, leading to deep mechanistic understanding of coupling principles and the ensuing activation process 3 . However, the majority of the GPCR-G protein complex structures have been determined in detergent micelles, with the exception of the recent structure of the dopamine D2 receptor (DRD2) in complex with G i (ref. 4 ), which was assembled in a nanodisc-based lipid environment. Now, Zhang et al. 5 have determined the structure of the NTSR1-Gα i1 -β 1 -γ 1 complex in circularized nanodiscs (Fig. 1), which provides interesting insights into the effect of the lipid context on receptor-G protein interactions and activation.NTSR1 is a rhodopsin-like class A GPCR that is activated by a tridecapeptide neurotransmitter called neurotensin. NTSR1 signaling is involved in oncogenic growth,