GPCRchimeraDB: A database of chimeric G-Protein Coupled Receptors (GPCRs) to assist their design

G-Protein Coupled Receptors (GPCRs) are membrane proteins implicated in numerous diseases that have been studied for decades. However, despite their significance, many GPCRs remain poorly characterized and untargeted by drugs. Chimeric GPCRs have emerged as valuable tools for elucidating GPCR function by facilitating the identification of signaling pathways, resolving structures, and discovering novel ligands of poorly understood GPCRs. Such chimeric GPCRs are obtained by merging a well-characterized and a less-well-characterized GPCR at the intracellular loops, leveraging knowledge transfer from the well-characterized GPCR. However, despite the 170 chimeric GPCRs engineered to date, the design process remains largely trial-and-error and lacks a standardized approach. To address this gap, we introduce GPCRchimeraDB ( https://www.bio2byte.be/gpcrchimeradb/ ), the first comprehensive database dedicated to chimeric GPCRs. It catalogs 170 chimeric receptors, identified through extensive literature review, and includes 1,758 natural GPCRs, enabling connections between chimeras and their parent receptors while facilitating the exploration of novel parent combinations. Both chimeric and natural GPCR entries are extensively described at the sequence, structural, and biophysical level through a range of visualization tools, with annotations from resources like UniProt and GPCRdb and predictions from AlphaFold, ESMFold and b2btools. Additionally, GPCRchimeraDB offers a GPCR sequence aligner and a feature comparator to investigate differences between natural and chimeric receptors as well as guidelines to support the design of novel chimeras. GPCRchimeraDB is therefore a resource to facilitate and optimize the design of new chimeras, so helping to gain insights into poorly characterized receptors and contributing to advances in GPCR therapeutic development.