GPCR Signalling – University of Copenhagen

GPCR Signalling

G protein selectivity and inhibitors

Left) GPCR-G protein selectivity is mainly determined by a ‘barcode’ (blue) on the G protein, which can be analysed in GPCRdb (Flock et al. Nature 2017). Mid) Crystal structure of the chimeric Gq/i protein in complex with the inhibitor YM-254890 (cyan carbons) (PDB:3AH8). Right) The bacterial cyclic depsipeptides YM-254890 and FR900359 are the only known specific inhibitors of the Gq protein subfamily, and were for the first time synthesised at UCPH (K. Strømgaard lab).

Upon ligand interaction, GPCRs elicit distinct cellular responses through the four G protein families; Gs, Gi/o, Gq and G12/13; and β–arrestin (also internalises receptors). A new paradigm in GPCR pharmacology, referred to as ‘biased signalling’, entails that a single receptor can exhibit ligand-dependent preference towards a certain signalling protein (profile) We just reached conceptual understanding – a biased agonist and its associated signalling protein bind and stabilise the same unique active receptor conformation/state. However, biased signalling has opened up a whole new research aiming to understand which biological/therapeutic responses are attributed to which signalling pathway, and the molecular mechanisms for design of tool/drugs avoiding undesired side-effects.

In a Nature publication, together with M. Babu, MRC Laboratory for Molecular Biology, UK, we contributed receptor determinants for GPCR-G protein selectivity using a novel comparative sequence method, and developed a G protein analysis resource. We also apply structure-based design to identify inhibitors of G proteins and β–arrestin. G protein inhibitor and analogous are synthesised in the K. Strømgaard lab and assayed in the H. Bräuner-Osborne group at the Department of Drug Design and Pharmacology. Furthermore, as part of a European industrial PhD student training network coordinated by J. Kristensen lab, we will soon (Feb 2018) set out to develop signal pathway-selective serotonin 5-HT2A receptor agonists, and will develop a public resource for biased ligands.

Selected publications

GPCR - G protein selectivity
Flock T, Hauser AS, Lund N, Gloriam DE, Balaji S, Babu MM
Selectivity determinants of GPCR-G protein binding
Nature 2017 May 18;545(7654):317-322

G protein inhibitors
Xiong XF, Zhang H, Underwood CR, Harpsøe K, Gardella TJ, Wöldike MF, Mannstadt M, Gloriam DE, Bräuner-Osborne H, Strømgaard K.
Total synthesis and structure-activity relationship studies of a series of selective G protein inhibitors.
Nat Chem. 2016 Nov;8(11):1035-1041