GPCRchimeraDB: A Database of Chimeric G Protein-Coupled Receptors (GPCRs) to Assist Their Design

Abstract

G protein-coupled receptors (GPCRs) are membrane proteins crucial to numerous diseases, yet many 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- and less-well-characterized GPCR at the intracellular limits of their transmembrane regions or intracellular loops, leveraging knowledge transfer from the well-characterized GPCR. However, despite the engineering of over 200 chimeric GPCRs 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 212 chimeric receptors, identified through literature review, and includes 1,755 class A 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 AlphaFold2 and b2btools. Additionally, GPCRchimeraDB offers a GPCR sequence aligner and a feature comparator to investigate differences between natural and chimeric receptors. It also provides design guidelines to support rational chimera engineering. 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.