CECAM workshop: "Understanding the function of G-Protein coupled receptors by atomistic and multiscale studies"

You can apply to participate and find all the relevant information (speakers, abstracts, program,...) on the event website: https://www.cecam.org/workshop-details/understanding-the-function-of-g-protein-coupled-receptors-by-atomistic-and-multiscale-studies-1288

*** REGISTRATION DEADLINE *** : 21st Ausgut 2024

Description
G protein-coupled receptors (GPCRs) are membrane proteins responsible for transducing a wide range of signals across the plasma membrane, regulating diverse functions through their activation or deactivation by endogenous and exogenous ligands [1,2]. These include metabolism, immune and inflammatory response, growth and differentiation, neurotransmission, olfaction, and vision, among others. It is therefore not surprising that GPCRs are the targets of ∼34% of prescribed drugs (accounting for ∼27% of the global market share) and are the primary focus of current pharmaceutical development, with more than 200 receptors to be explored clinically [3].
Notwithstanding the pharmacological relevance of these proteins and the recent efforts, a comprehensive characterisation of GPCR function is still lacking. The accepted hypothesis for GPCR activation suggests that binding of an agonist molecule to the extracellular orthosteric site induces an outward motion of the cytoplasmic part of transmembrane helix 5 (TM5) and 6 (TM6) via allosteric effects [2-4]. However, recent experimental and computational evidence indicates that some GPCRs may be activated via a tandem process in which a G protein breaks an intracellular salt bridge (“ionic lock”) between TM3 and TM6, while an agonist stabilises the receptor's active conformation [5-7]. This synergistic interaction is essential for GPCR activation since the absence of either the G protein or the agonist makes the overall mechanism thermodynamically unfavourable [7]. Overall, the GPCR signalling mechanism is regulated by subtle conformational changes involving several microswitches and pairwise interactions - such as the TM3-TM6 ionic lock - which are difficult to track and correlate with macroscopic effects. The scenario has been further complicated by the discovery of compounds that can promote or hinder GPCR activation without binding to the orthosteric site [8-10], as well as small molecules capable of promoting specific signalling pathways, a phenomenon known as biased signalling [10-14]. These findings suggest the existence of alternative, perhaps even more nuanced, conformational mechanisms that regulate GPCR activity and remain to be elucidated. It is worth noting that the native environment can further modulate these equilibria via protein-protein or lipid-protein interactions [10,15-18].
Given the intricacy of the factors governing GPCR activation, computational techniques might serve as a strategy for investigation since they can provide an atomistic description of the underlying interactions. Indeed, computational studies helped clarify many previously described aspects [1-2, 7, 10, 12, 14-17, 19]. Nevertheless, there is still much work to be done. Understanding GPCR activation mechanisms is crucial for rationalising drug structure-activity relationships.  Biased signalling represents a promising area with significant implications for clinical pharmacology and therapeutics, but its underlying molecular mechanism remains opaque. Elucidating how the lipidic environment and GPCR localisation influence signalling pathways may facilitate the development of novel therapeutics. 
These topics will form the core of the discussions planned for our workshop, which hold substantial medical, economic, and social implications due to the pharmacological relevance of these receptors. Bringing together the most prominent GPCR scientists - from both experimental and computational backgrounds - will facilitate a positive and productive exchange that we anticipate will push the boundaries of our GPCR knowledge. Indeed, the last edition of this workshop - held in 2022 - resulted in fruitful collaborations, and the speakers we contacted for the second edition were enthusiastic to contribute once again. By establishing recurring, biannual meetings, we aim to create a robust network that can serve as a reference point for students and early-stage scientists interested in connecting with GPCR experts.

References
1. Hilger, D., Masureel, M. & Kobilka, B. K. Structure and dynamics of GPCR signaling complexes. Nature Structural & Molecular Biology 25, 4–12 (2018).
2. Latorraca, N. R., Venkatakrishnan, A. J. & Dror, R. O. GPCR Dynamics: Structures in Motion. Chemical Reviews 117, 139–155 (2016).
3. Hauser, A. S., Attwood, M. M., Mathias Rask-Andersen, Schiöth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. 16, 829–842 (2017).
4. Weis, W. I. & Kobilka, B. K. The Molecular Basis of G Protein-Coupled Receptor Activation. Annu. Rev. Biochem. 87, 897–919 (2018).
5. Manglik, A. et al. Structural Insights into the Dynamic Process of β 2 -Adrenergic Receptor Signaling. Cell 161, 1101–1111 (2015).
‌6. Gregorio, G. G. et al. Single-molecule analysis of ligand efficacy in β2AR–G-protein activation. Nature 547, 68–73 (2017).
7. Mafi, A., Kim, S.-K. & Goddard, W. A. The dynamics of agonist-β2-adrenergic receptor activation induced by binding of GDP-bound Gs protein. Nature Chemistry 1–11 (2023).
‌8. Wold, E. A., Chen, J., Cunningham, K. A. & Zhou, J. Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts. Journal of Medicinal Chemistry 62, 88–127 (2018).
‌9. Slosky, L. M., Caron, M. G. & Barak, L. S. Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery. 42, 283–299 (2021).
10. Thal, D. M., Glukhova, A., Sexton, P. M. & Christopoulos, A. Structural insights into G-protein-coupled receptor allostery. Nature 559, 45–53 (2018).
‌11. Smith, J. S., Lefkowitz, R. J. & Rajagopal, S. Biased signalling: from simple switches to allosteric microprocessors. Nature Reviews Drug Discovery 17, 243–260 (2018).
12. Wootten, D., Christopoulos, A., Marti-Solano, M., Babu, M. M. & Sexton, P. M. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Nature Reviews Molecular Cell Biology 19, 638–653 (2018).
13. Wall, M.J., Hill, E., Huckstepp, R. et al. Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression. Nat Commun 13, 4150 (2022).
14. Faouzi, A., Wang, H., Zaidi, S.A. et al. Structure-based design of bitopic ligands for the µ-opioid receptor. Nature 613, 767–774 (2023).
15. Duncan, A. L., Song, W. & Sansom, M. S. P. Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations. Annual Review of Pharmacology and Toxicology 60, 31–50 (2020).
16. Sarkar, P., Chattopadhyay, A. Cholesterol interaction motifs in G protein-coupled receptors: Slippery hot spots? WIREs Syst Biol Med.,12:e1481 (2020).
‌17. Milligan, G., Ward, R. J. & Marsango, S. GPCR homo-oligomerization. Current Opinion in Cell Biology 57, 40–47 (2019).
18. Huang, B., Celsey M. St. Onge, Ma, H. & Zhang, Y. Design of bivalent ligands targeting putative GPCR dimers. Drug Discovery Today 26, 189–199 (2021).
19. Hollingsworth, S. A. & Dror, R. O. Molecular Dynamics Simulation for All. Neuron 99, 1129–1143 (2018).