Dr. Xavier Deupi i Corral

Communication with the environment is a key aspect of life. At the cellular level, this task can be carried out by proteins embedded in the cell membrane, which are exposed both to the extracellular environment and to the cytoplasm, and can thus act as 'cellular intercoms'. Due to their diversity and prevalence, G protein-coupled receptors (GPCRs) are one of the most important groups of such signalling membrane receptors.

In essence, binding of extracellular ligands to GPCRs results in the recruitment and activation of intracellular G proteins, arrestins, and many other partners. This mechanism allows the information encoded in diverse endogenous ligands or pharmaceutical drugs to be translated into a complex set of intracellular protein-protein interactions that ultimately produce a concerted cellular signalling response (e.g. release of second messengers or activation of enzymes). Thus, these receptors are essential in cell physiology – underlying processes as different as vision, smell, neurotransmission, and the response to hormones – and their malfunction commonly leads to disease. GPCRs are therefore a leading class of pharmaceutical targets, with around 30% of prescribed drugs acting through this family of proteins. However, we are just beginning to understand how GPCRs and their intracellular effectors interact to generate these signalling cascades. In my group, we study the structural and dynamic basis of GPCR signalling, by combining molecular simulations and modelling with experimental data. For example, we have recently studied the structural elements that direct G protein and β-arrestin interactions at the melatonin MT2 receptor (Plouffe et al., ACS Pharmacol. Transl. Sci. 2022), how the chemokine receptor CCR5 is activated by its agonist (Isaikina et al., Sci. Adv. 2021), and how cyclic peptides act as molecular glues to stabilise G protein heterotrimers (Mühle et al., PNAS 2025).

Opsins are light-activated Class A GPCRs that mediate both visual and non-visual photoresponses across the animal kingdom. Among them, rhodopsin, the dim-light photoreceptor of the retina, has been a paradigm for the study of GPCR structure and function: for years it was the only GPCR with a high-resolution structure, and much of what we know about GPCR activation was first learned from it (Deupi, Biochim. Biophys. Acta 2014). It shares a common activation mechanism with the rest of the Class A family, despite some interesting differences (Deupi & Kobilka, Physiology 2010). In opsins, light isomerises a covalently bound retinal chromophore, and the surrounding protein finely tunes the colour of light each one absorbs. This spectral tuning has been reshaped repeatedly over evolution to suit the light environments in which different organisms live, making opsins a rich system in which to study the mechanisms and evolution of GPCR structure and function. In my group, we combine structural modelling, molecular dynamics simulations, and quantum-mechanics calculations to study how opsins absorb and respond to light. For example, we have described a novel chloride counterion used for spectral tuning in coral opsins (Sakai et al., eLife 2025), the convergent evolution of rhodopsin structure between vertebrates and box jellyfish (Gerrard et al., PNAS 2018), and the excited-state photophysics of the conjugated chromophores related to retinal (Sen & Deupi, ACS Phys. Chem. Au 2024).

We use the same structural and computational tools to help design molecules that act on receptors for diagnosis and therapy. Specifically, in collaboration with researchers at PSI's Center for Radiopharmaceutical Sciences (CRS), we study radioligands — molecules that carry a radionuclide to a chosen target. Designing effective radioligands requires understanding, at the molecular level, how they recognise their target and how that recognition can be optimised for affinity, selectivity, and favourable distribution in the body. For example, we have contributed structure-based modelling to the development of radiopeptides directed against the urokinase receptor uPAR for radionuclide therapy (Vaccarin et al., Eur. J. Nucl. Med. Mol. Imaging 2025), and of ACE2-selective radiopeptides for imaging the SARS-CoV-2 entry receptor (Beyer et al., EJNMMI Research 2023).

Plouffe B, Karamitri A, Flock T, et al. Structural elements directing G proteins and β-arrestin interactions with the human melatonin type 2 receptor revealed by natural variants. ACS Pharmacol. Transl. Sci. 2022. https://doi.org/10.1021/acsptsci.1c00239

Isaikina P, Tsai C-J, Dietz N, et al. Structural basis of the activation of the CC chemokine receptor 5 by a chemokine agonist. Sci. Adv. 2021. https://doi.org/10.1126/sciadv.abg8685

Mühle J, Alenfelder J, Rodrigues MJ, et al. Cyclic peptide inhibitors function as molecular glues to stabilize Gq/11 heterotrimers. PNAS 2025. https://doi.org/10.1073/pnas.2418398122

Deupi X. Relevance of rhodopsin studies for GPCR activation. Biochim. Biophys. Acta Bioenerg. 2014. https://doi.org/10.1016/j.bbabio.2013.09.002

Deupi X, Kobilka BK. Energy landscapes as a tool to integrate GPCR structure, dynamics, and function. Physiology 2010. https://doi.org/10.1152/physiol.00002.2010

Sakai Y, et al. Coral anthozoan-specific opsins employ a novel chloride counterion for spectral tuning. eLife 2025. https://doi.org/REPLACE-WITH-SAKAI-DOI

Gerrard E, Mutt E, Nagata T, et al. Convergent evolution of tertiary structure in rhodopsin visual proteins from vertebrates and box jellyfish. PNAS 2018. https://doi.org/10.1073/pnas.1721333115

Sen S, Deupi X. Study of photoselectivity in linear conjugated chromophores using the XMS-CASPT2 method. ACS Phys. Chem. Au 2024. https://doi.org/10.1021/acsphyschemau.4c00065

Vaccarin C, Beyer D, Schmid JV, et al. Optimizing uPAR-targeting radiopeptides for improved tissue distribution: progress towards radionuclide therapy. Eur. J. Nucl. Med. Mol. Imaging 2025. https://doi.org/10.1007/s00259-025-07602-7

Beyer D, Vaccarin C, Deupi X, et al. A tool for nuclear imaging of the SARS-CoV-2 entry receptor: molecular model and preclinical development of ACE2-selective radiopeptides. EJNMMI Research 2023. https://doi.org/10.1186/s13550-023-00979-2