Orphan Receptor Research

Orphan receptors are a class of proteins that do not have a known ligand. While most receptors bind to specific ligands to become activated, orphan receptors do not appear to follow this trend. Instead, these receptors are believed to be activated by a variety of different mechanisms. For example, some orphan receptors may be constitutively active, while others may require the presence of multiple ligands to become activated. Despite their name, orphan receptors are pretty common. It is estimated that over 30% of all human proteins are orphan receptors. While the exact function of these proteins is still unknown, researchers believe they play an essential role in cell signaling and development. Orphan receptors have also been implicated in several diseases, including cancer and diabetes. As a result, orphan receptors are the subject of intense research interest.

Fig.1 Expression and function of receptor-related orphan receptors (RORs) in the tumor microenvironment. (Fan, et al., 2018)

Orphan G Protein-Coupled Receptors (GPCRs)

GPCRs represent the most prominent family of transmembrane receptors responsible for the transduction of a diverse array of extracellular signals, including light, Ca²⁺, odorants, amino acids, nucleotides, peptides, fatty acid derivatives, and various polypeptide ligands. In general, ligand binding to the GPCR results in a conformational change that activates intracellular heterotrimeric G proteins. These proteins mediate a variety of intracellular responses that regulate cell functions.

Fig.2 G protein-coupled receptor (GPCR) signaling pathway. (Jo & Jung, 2016)

Most G protein-coupled receptors (GPCRs) are discovered through sequence similarity. However, these lack endogenous ligands and are, therefore, orphan GPCRs. While molecular biology and bioinformatics techniques have enabled identifying orphan GPCRs, finding their endogenous ligands has been challenging. This research led to a reverse pharmacology approach, which uses orphan GPCRs as targets to identify endogenous ligands. This approach has been so successful that about 300 GPCRs have been de-orphaned over 20 years. Many ligands matching orphan GPCRs are already known, but more than a dozen are newly discovered, notably nine new neuropeptide families. These new neuropeptides have enriched our understanding of several critical behavioral responses, particularly the central regulation of food intake. There are still 100 orphan GPCRs that may bind to endogenous non-chemosensory ligands. This article reviews the history of orphan GPCR research, discussing some successes and current difficulties.

Fig.3 Schematic representation of current deorphanization approaches. (Levoye & Jockers, 2008)

Orphan Nuclear Receptors

Nuclear receptors are ligands-dependent transcription factors that have important roles in several biological processes, including cell proliferation, differentiation, and cellular homeostasis. Members of the nuclear receptor superfamily include the well-known endocrine receptors, the adopted orphan receptors, for which ligands have been identified in recent years, and the orphan receptors, ligands of which have not yet been identified. Identifying selective small molecule ligands is one of the major goals of orphan nuclear receptor research, which will make new therapeutic interventions available for various human diseases.

Fig.4 Structure-function domains and the superfamily members of nuclear receptors. (Shi, 2007)

References

1. Fan, J.; et al. Retinoic acid receptor-related orphan receptors: critical roles in tumorigenesis. Frontiers in Immunology. 2018, 9: 1187.
2. Jo, M.; Jung, S. Engineering therapeutic antibodies targeting G-protein-coupled receptors. Experimental & Molecular Medicine. 2016, 48, e207.
3. Levoye, A.; Jockers, R. Alternative drug discovery approaches for orphan GPCRs. Drug Discovery Today. 2008, 13
4. Shi, Y.H. Orphan nuclear receptors in drug discovery. Drug Discovery Today. 2007, 12(11-12): 440-445.