Designing chimeric G-Protein Coupled Receptors: Past, Present and Future.

Despite being targeted by ~35% of the approved drugs, the majority of G-Protein Coupled Receptors (GPCRs) remain undrugged, even when strongly implicated in diseases with no existing therapy. Much of the difficulty in targeting GPCRs can be attributed to their innate conformational flexibility and low shared sequence identity. Chimeric GPCRs, typically the merger of well- and not well-characterized GPCRs, can improve our understanding of these receptors. They can help in elucidating the 3D structures of GPCRs, enhancing our knowledge of their biological pathways, and identifying new ligand binders.
So far, over 150 chimeric GPCRs have been successfully engineered. However, designing chimeras remains challenging as it requires the identification of equivalent regions at the sequence, structural and biophysical level where the parent GPCRs can be merged. Despite their relevance, no "golden rules" for chimeric GPCR design have been established yet, perhaps due to the lack of overview and annotations in the previous designs. To address this, we developed GPCRchimeraDB (https://www.bio2byte.be/gpcrchimeradb/), the first comprehensive database that gathers, describes, and visualizes previously designed chimeric GPCRs to facilitate the creation of novel ones. GPCRchimeraDB contains natural and chimeric GPCRs, compiled through an extensive literature review, and each entry is described at the sequence, structural, and biophysical levels. Feature comparisons between the chimeras and their parent GPCRs is available as well as, a highly accurate sequence alignment tool that surpasses the alignment quality of GPCRdb for non-conventional GPCRs. Finally, an overview of the rules required to obtain successful chimeras is provided.