Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands

By P. Joost, A. Methner. 2002

227 citations recorded by the source corpus.

BackgroundG-protein-coupled receptors (GPCRs) are the largest and most diverse family of transmembrane receptors. They respond to a wide range of stimuli, including small peptides, lipid analogs, amino-acid derivatives, and sensory stimuli such as light, taste and odor, and transmit signals to the interior of the cell through interaction with heterotrimeric G proteins. A large number of putative GPCRs have no identified natural ligand. We hypothesized that a more complete knowledge of the phylogenetic relationship of these orphan receptors to receptors with known ligands could facilitate ligand identification, as related receptors often have ligands with similar structural features.ResultsA database search excluding olfactory and gustatory receptors was used to compile a list of accession numbers and synonyms of 81 orphan and 196 human GPCRs with known ligands. Of these, 241 sequences belonging to the rhodopsin receptor-like family A were aligned and a tentative phylogenetic tree constructed by neighbor joining. This tree and local alignment tools were used to define 19 subgroups of family A small enough for more accurate maximum-likelihood analyses. The secretin receptor-like family B and metabotropic glutamate receptor-like family C were directly subjected to these methods.ConclusionsOur trees show the overall relationship of 277 GPCRs with emphasis on orphan receptors. Support values are given for each branch. This approach may prove valuable for identification of the natural ligands of orphan receptors as their relation to receptors with known ligands becomes more evident.

Subfields: Molecular Biology, Sensory Systems

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Citations in the corpus

Protein 3D Structure Computed from Evolutionary Sequence Variation (2011, background): “This important class of membrane proteins has 7 helices and the PFAM family from which the distance restraints are inferred contains many subfamilies of class A G-protein coupled receptors [56].”
The G protein-coupled receptor subset of the rat genome (2007, background): “We found the number of human orphan Rhodopsin receptors to be 65 while the number was 84 in 2002 [61] suggesting that the current rate of de-orphanization is higher than that for the discovery of members of this family.”
Specific Recruitment of Antigen-presenting Cells by Chemerin, a Novel Processed Ligand from Human Inflammatory Fluids (2003, background): “ChemerinR is structurally and evolutionary related to the C5a and C3a receptors, the prostaglandin D2 receptor CRTH2, and the orphan GPR1 receptor ( 20 ).”
International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy (2006, background): “Several of the currently available orphan GPCR sequences are structurally related to P2Y receptors (Lee et al., 2001; Wittenberger et al., 2001; Joost and Methner, 2002; Vassilatis et al., 2003): GPR87, H963, and GPR34.”
3D Protein Structure Predicted from Sequence (2011, unknown): “This important class of membrane proteins has 7 helices and the PFAM family from which the distance restraints are inferred contains many subfamilies of class A G-‐protein coupled receptors[54].”
The Repertoire of G-Protein–Coupled Receptors in Fully Sequenced Genomes (2005, background): “The human repertoire of GPCRs has recently been described in detail (Joost and Methner 2002; Fredriksson et al., 2003c; Vassilatis et al., 2003), although there are still additional new human GPCRs being annotated (Fredriksson et al., 2003a,b).”
Anatomical profiling of G protein-coupled receptor expression (2008, unknown): “Although in vivo roles have been defined for many of the approximately 370 nonodorant GPCRs in mice and humans, the expression and function of many such receptors are incompletely characterized, and a significant fraction remain orphans (Fredriksson et al., 2003; Fredriksson and Schioth, 2005; Hill ”