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Multi-disciplinary approach to investigate the molecular basis of G protein signalling

 

Graham Ladds PhD - Group Leader

 
Tel:  +44 (0)1223 334020 (office)
+44 (0)1223 334028 (lab)

 

 

Keywords:

G proteins, GPCRs, Signal Bias, cell signalling, RAMPs, computational modelling, RGS proteins, mathematical simulations.

Investigator Biography

Graham studied Biochemistry at the University of Birmingham before completing a PhD in yeast pheromone signalling with John Davey at Warwick. He continued to work at Warwick as a post-doc studying pro-hormone convertases before securing a 5-year independent fellowship funded through the NHS. This project enabled him to return to his interest of GPCRs. He was appointed a lecture at Warwick in 2006. He is a full member of the British Pharmacology Society and regularly attends meetings both in the UK and Australia. He has a long-standing collaboration with Dr Simon Dowell at GlaxoSmithKline. His group is interested in RAMP-mediated signalling bias of family B GPCRs.

Lab members

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Research Summary

Our research uses a multi-disciplinary approach to investigate the molecular basis of G protein signalling. We combine computational modelling with in vivo experimentation using model organisms to probe the dynamics of G protein action.

Our current focus is on the molecular mechanisms that family B G protein-coupled receptors (GPCRs) utilise to engender signalling bias. Specifically we are establishing the extent and consequences of receptor modifying activity proteins (RAMPs) association with the human family B GPCRs. Many physiologically important hormones and neurotransmitters act via family B GPCRs. These include substances such as GLP-1 and glucagon, relevant to diabetes and other metabolic disorders especially common in the elderly. RAMPs are found throughout the body. However, until recently, the consequences of RAMP-receptor interactions remained unknown. A recent study of two receptors has shown that RAMPs have important consequences for the way they function and we are now extending these studies to all 15 family B GPCRs.

Our initial studies use yeast cells but we aim to extend them to mammalian systems and eventually we aim to explore the physiological consequences of these interactions using sophisticated in-vivo models. Furthermore, it is likely that the association of the RAMP with a receptor will create a unique architecture of the resulting complex that can be selectively targeted by drugs.

Key references

1. Shaw, W.M., Yamauchi, H., Mead, J., Gowers, G.F., Oling, D., Larsson, N., Wigglesworth, M.*, Ladds, G.* and Ellis, T.* (2019) Engineering a model cell for rational tuning of GPCR signalling Cell. 177: 782-796.

2. Stamatis, D., Lagarias, P., Barkan, K., Vrontake, E., Ladds, G.*and Kolocouoris, A., (2019) Structural Characterization of Agonist Binding to A3Adenosine Receptor through Biomolecular Simulations and Mutagenesis Experiments. J. Med. Chem.doi: 10.1021/acs.jmedchem.9b01164

3. Bridge, L., Mead, J., Frattini, E., Winfield, I., and Ladds, G.(2018) Modelling and simulation of biased agonism dynamics at a G protein-coupled receptor. J. Theoretical. Biol.7: 44-65.

4. Weston, C., Winfield, I., Harris, M., Hodgson, R., Shah, A., Dowell, S.J., Moarec, J-C, Woodlock, D.A., Reynolds, C.A., Poyner, D.R., Watkins, H.A. and Ladds, G. (2016) RAMP-directed G protein signaling specificity for the calcitonin gene-related peptide family of receptors. J. Biol. Chem. pii: jbc.M116.751362.

5. Knight, A., Hemmings, J.L., Frenguelli, B.G., Dowell, S.J., Lochner, M. and Ladds, G. (2016) Discovery of Novel Adenosine Receptor Agonists that Exhibit Subtype Selectivity. J. Med Chem. 59: 947.