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

Dr Graham Ladds

Professor Graham Ladds  - Group Leader

Professor in Receptor Pharmacology

Email: grl30@cam.ac.uk

Tel:  +44 (0)1223 334020 (office)

+44 (0)1223 34062 (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 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 progressed through the ranks at Warwick become an Associate Professor before leaving in 2015 to join the Department of Pharmacology at Cambridge, where he is also a Fellow of St John’s College. In 2020, he was promoted to a Readership in Receptor Pharmacology and was elected a Fellow of the British Pharmacological Society.

His research group use a combination of pharmacological investigations and mathematical modelling to study factors that control agonist bias at GPCRs. These investigations have enabled him to foster strong collaborations with the pharmaceutical industry (GSK, Takeda and Firmenich) which have recently been enhanced though him being awarded a Royal Society Industry Fellowship to collaborate with AstraZeneca.

Lab members

Dr Abigail Pearce  - Dr David Prole - Dr Aneesh Chandran- Dr Emily Taylor - Ms Anjana Saji -  Mr Theo Redfern-Nichols - Mr Edward Wills - Ms Claudia Sisk - Ms Jing Li - Ms Milena Malcharek - Mr Aman Khan - Mr Venkat Vege - Mr Darius Hoven - Ms Amy Davies - Mr Tim Noel - Mr Aaron Dexter - Mr Micheal Collins

The group merged with Professor Colin W Taylor's group following his retirement in 2022. His page can be found here.

Research Summary

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

Our group studies the members of both the Class A and Class B1 G protein-coupled receptors (GPCRs),superfamilies. We are specifically interesting in understanding the concept of agonist-induced signalling bias and factors which regulate this process. For the Class B1 G protein-coupled receptors, which include GLP-1, GIP, glucagon, CGRP etc we study the extent and consequences of receptor modifying activity proteins (RAMPs). These proteins can bias the signalling outcomes for these important receptors relevant to diabetes and other metabolic disorders especially common in the elderly. While RAMPs are found throughout the body. However, until recently, the consequences of RAMP-receptor interactions remained unknown. Our recent studies have shown that RAMPs have important consequences for the way they function and we are now extending these studies to all 15 Class B1 GPCRs.

For the Class A GPCRs, we are investigating, using multidisciplinary approaches how agonists activate different G proteins. This work has significant therapeutic potential as demonstrated by our studies with BnOCPA, a novel selective Adenosine A1 receptor agonist that engenders pain relief without cardiovascular and respiratory issues. 

All our studies are aimed at reducing on-target but unwanted side effects of many drugs targeting GPCRs. Our leading expertise in BRET-based assays enable us, at the molecular level, to decipher precise agonist-receptor-G proteins interactions and their therapeutic impact.

Finally, we continue the legacy of Professor Taylor by having ongoing research projects studying the IP3 Receptor and intracellular Calcium release.

Key references

Huang, X., ….. Ladds, G. (2024) Hit-to-Lead Optimization of Heterocyclic Carbonyloxycarboximidamides as Selective Antagonists at Human Adenosine A3 Receptor. J Med Chem 67, 13117-13146.

Jones, A., …… Ladds, G. & Nietlispach, D. (2024) Structurally similar G protein complexes with β1-adrenergic receptor active state show differential binding kinetics, mediating selectivity. Nat Comms. 15, 1334.

Guida, C., .. Ladds, G.* & Rorsman, P.* (2024) GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion. Diabetologia 67:528-546

Marti-Solano, M., Crilly, S.E., Malinverni, D., …Ladds, G. …. Babu, M.M. (2020) Combinatorial expression of functionally distinct GPCR isoforms can diversify receptor signalling response. Nature 588(7838):E24. doi: 10.1038/s41586-020-2999-9.

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. (F1000Prime recommended).

Funding

Research in the lab is funded by the following sources:

  • AstraZeneca
  • Medical Research Council
  • Engineering and Physical Sciences Research Council
  • The Leverhulme Trust
  • BBSRC
  • Takeda