Orphan receptor

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An orphan receptor is a receptor whose natural binding molecule (ligand) is not known. If scientists later discover a ligand for it, the receptor becomes adopted (also called de-orphanized). The term orphan ligand refers to a molecule whose receptor hasn’t been found yet.

Orphan receptors show up in two families: G protein-coupled receptors (GPCRs) and nuclear receptors. Examples include the nuclear receptors farnesoid X receptor (FXR) and TGR5, both activated by bile acids, making them adopted. Other adopted nuclear receptors are liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR).

An example of an orphan site is the PCP binding site in the NMDA receptor, where the drug PCP acts but no endogenous ligand is known.

GPCRs with unknown ligands are usually labeled as GPR followed by a number, such as GPR21. About 100 GPCR genes remain as orphans.

Historically, receptors were found by finding the ligands first, but now researchers also use methods like reverse pharmacology, screening of cDNA libraries, and whole-genome sequencing to identify receptors by sequence similarity even before their ligands are known.