GPCRs make up the largest family of human membrane proteins and of drug targets. Decades of experimental and structural work have revealed how these receptors operate at the molecular level, but this work has covered only a fraction of the superfamily, leaving the majority of receptors underexplored. To address this problem, we developed the GPCR Evolution Database, gpcrevolution.org, an open-access resource that makes high-quality evolutionary analysis of GPCRs available to every laboratory. Through our database, each human receptor can be examined against its own orthologs, where per-residue conservation reveals the sites that evolution has protected throughout that receptor’s history. These orthologous lineages can then be compared with their paralogs within the same GPCR family, to distinguish residues shared across paralogous lineages, which likely support ancestral functions, from the lineage-specific residues that underlie functional differentiation between receptor subtypes. The database provides ortholog sets, multiple sequence alignments, phylogenetic trees and per-residue conservation scores for over 800 human GPCRs. The resource presents these through interactive conservation plots, sequence logos and snake plots, and provides tools for comparing conservation across two or more paralogous lineages. Overall, the GPCR Evolution Database provides the data and tools for researchers to examine GPCR function through an evolutionary lens, allowing molecular insights from well-studied receptors to be extended to their underexplored relatives.
BACKGROUND AND PURPOSE
G protein-coupled receptors (GPCRs) are integral membrane proteins that mediate physiological processes by enabling cells to detect and respond to diverse stimuli. Although many subfamily-specific functional hotspots have been described, the family-wide determinants of common and subfamily-specific functions remain incomplete.
EXPERIMENTAL APPROACH
Here, we developed an evolutionary framework utilizing conservation within orthologs and variation across paralogs to classify positions as common residues (CRs) or selective residues (SRs).
KEY RESULTS
Common residues (CRs) cluster in sites linked to structural stability and activation, whereas SRs concentrate at selective interfaces involved in ligand and transducer binding. SR distributions across families revealed that some classes mainly diversify through changes in ligand-recognition sites, whereas others through changes at transducer-binding interfaces. We also uncovered CRs involved in family-specific and cross-family motifs, including conserved disulfide bridges and cholesterol-contact sites.
CONCLUSIONS AND IMPLICATIONS
Together, these findings provide an evolutionary blueprint of family-wide features, reinforce known associations and deliver testable hypotheses that are especially valuable for understudied families.
Berkay Selçuk, Gunnar Schulte, I. Zhulin et al.· British Journal of Pharmacol...· 0 citations
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