Key Points
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The elucidation of the primary structure of the first identified G-protein-coupled receptor (GPCR) rhodopsin 25 years ago was a key step in the development of the concept of a GPCR superfamily. Now, data from our recent mining of the human genome suggests that humans have at least 799 full-length GPCRs, making them the largest superfamily of membrane-bound receptors.
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Members of the GPCR superfamily are diverse in their primary structure, and classification of these receptors has been made on the basis of phylogenetic criteria. This showed that most of the human GPCRs can be grouped into five main families: Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2 and Secretin.
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The Rhodopsin family is the largest family of GPCRs, containing ∼670 full-length human receptor proteins. They can be divided into four groups and bind to a wide range of ligands. Their diversity is attributed to differences within the transmembrane regions. So far, the only crystal structures available for the transmembrane regions of GPCRs are the bovine rhodopsin receptor and the human β2-adrenoceptor (ADRB2). These two structures have aided the understanding of how GPCRs are activated and in homology modelling.
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The Adhesion family is the second largest and can be subdivided into eight subgroups. They are rich in functional domains and most have long and diverse N termini. The N termini may contain domains that are also found in other proteins (for example, lectin, cadherin), and the number and structure of these domains has been shown to have an important role in the specificity of the receptor–ligand binding interactions.
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The Secretin family is small and share between 21–67% sequence identity. They all have an extracellular hormone-binding domain and bind peptide hormones.
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The Glutamate family consists of 22 human proteins, and most members bind to their respective endogenous ligand within the N-terminal region.
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The frizzled receptors bind the family of Wnt glycoproteins and are implicated in cancer development. The Taste2 receptors can be divided into five subgroups and have great sequence diversity. This diversity may explain how a limited number of receptors can distinguish between the thousands of bitter compounds that humans can detect.
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GPCRs are one of most common targets of therapeutic drugs so far, with drugs available that target at least 46 receptors in three of the families: Rhodopsin, Secretin and Glutamate. It is proposed that 323 GPCRs could also represent drug targets, and ∼150 are still orphans.
Abstract
G protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and also the targets of many drugs. Understanding of the functional significance of the wide structural diversity of GPCRs has been aided considerably in recent years by the sequencing of the human genome and by structural studies, and has important implications for the future therapeutic potential of targeting this receptor family. This article aims to provide a comprehensive overview of the five main human GPCR families — Rhodopsin, Secretin, Adhesion, Glutamate and Frizzled/Taste2 — with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery.
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Acknowledgements
We thank J.-P. Pin, R. Bywater, D. Rognan, K. Kullander and C. Pickering for valuable comments on the manuscript. We also thank R. Fredriksson for fruitful discussions on the topic. This study was supported by The Swedish Research Council and the Swedish Brain Foundation.
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Glossary
- Phylogenetic classification
-
The classification of protein sequences that is based on primary sequence similarity.
- Sequence hidden Markov model
-
A statistical representation of a multiple sequence alignment. The model can later be used as a search tool to identify similar sequences.
- Bilateral
-
The body of a bilateral animal is symmetrical around the midline, which results in two almost mirror image halves. The Bilateria can be divided into two main groups: deuterostomes and proto-stomes, in which mammals belong to the former.
- Pharmacophore
-
The steric and electronic features of a ligand that are necessary to ensure optimal interactions with a biological target structure and to trigger (or to block) its biological response.
- Allosteric ligands
-
Ligands binding to a site that is separate from the site of the endogenous ligand/ligands.
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Lagerström, M., Schiöth, H. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat Rev Drug Discov 7, 339–357 (2008). https://doi.org/10.1038/nrd2518
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DOI: https://doi.org/10.1038/nrd2518
