The Butterfly Effect on GPCRs

Abstract

Numbers speak for themselves, and that's why every single G protein-coupled receptor (GPCR) related work starts with the same sentence: "GPCRs are very important pharmacological entities, as evidenced by the fact that almost 40% of the currently FDA-approved marketed drugs target one of them." In other words, the numerous drug discovery efforts made in the GPCR field have enabled the design of 27 out of the 100 top-selling small-molecule drugs in 2020 (Persechino et al., 2022). As of 2018 they already accounted for over $180 billion in global annual sales (Hauser et al., 2018). The aim of this thesis has been to combine experimental, structural, and computational methods to study GPCRs in a cross-cutting fashion, thus providing new insights about their behavior to the field._x000D_ GPCRs are located in the cell membrane where they sense a wide variety of extracellular molecules and transduce their signal into the interior of the cell. The butterfly effect is the idea that a small change can have a large, non-linear impact on dynamic systems. Because GPCRs are dynamic proteins, small-scale structural variations might promote large functional consequences. This thesis has been organized in three chapters, each of them addressing a different modification on the GPCR system._x000D_ Chapter 1 focuses on the characterization of small changes in both the ligand structure and the amino acids forming the ligand binding cavity, which have huge impact in the functional activity. Chapter 2 highlights the characterization of a subtle modification on the receptor sequence, although may seem harmless a priori, that leaded to significant structural rearrangements and functional effects. Finally, Chapter 3 explored the allosteric effects due to the formation of oligomers constituted by different (hetero) receptor protomers._x000D_ Altogether, the results obtained in this thesis allow to conclude that the sensitivity to small changes needs to be seriously considered when studying and pharmacologically targeting GPCRs. Additionally, GPCR dimers can greatly contribute in new therapeutic strategies to improve disease-specific treatments and avoid undesirable side effects._x000D_ This thesis outcome highlights how the combination of experimental, biophysical and computational techniques is fundamental for the detailed understanding of the human biology.

Date of Award	5 Dec 2023
Original language	English
Supervisor	Leonardo Pardo Carrasco (Director) & Gemma Navarro Brugal (Director)