orthosteric

Orthosteric refers to the primary binding site on a receptor or transporter where the endogenous ligand binds to initiate signaling. This site, often called the orthosteric site, is the canonical locale for natural activation or inhibition of the receptor by its endogenous chemical messenger, such as a neurotransmitter or hormone. The term contrasts with allosteric sites, which are distinct regions on the same protein where other molecules can bind and modify receptor activity without occupying the orthosteric site.

Orthosteric ligands include agonists that activate the receptor and antagonists that block it by competing with the endogenous ligand for the binding site. Because many receptors—especially G protein-coupled receptors and ligand-gated ion channels—have orthosteric pockets that are structurally conserved across subtypes, orthosteric ligands often exhibit limited subtype selectivity. This has driven interest in allosteric ligands, which bind elsewhere and can provide greater specificity or different modulatory effects, including ceiling effects or biased signaling.

Examples help illustrate the concept. Acetylcholine is the endogenous orthosteric ligand for both nicotinic and muscarinic acetylcholine receptors. Drugs such as nicotine act as orthosteric agonists at nicotinic receptors, while atropine acts as an orthosteric antagonist at muscarinic receptors. In contrast, allosteric modulators bind at separate sites and alter the receptor’s response to the endogenous ligand without directly activating or inhibiting through the orthosteric site.