Serotonin receptors are targets for drugs treating depression, obesity, and migraine headaches. Crystal structures of two serotonin receptor subtypes bound to antimigraine medications or a precursor of LSD reveal how subtle differences in ligand binding cause substantial differences in receptor signaling and biological responses. The structures show that the same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which receptor it binds.
Two research teams independently determined the crystal structures of two serotonin receptors bound to antimigraine drugs or a precursor of LSD. The structures show that subtle differences in how ligands bind to these receptors lead to substantial differences in the signals generated and the resulting biological responses. The same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which specific receptor it binds to.
Deleting a single carbon atom (C20) from the complex plant metabolite salvinorin A stabilizes its molecular skeleton, simplifies its laboratory synthesis to just 10 steps, and preserves its high affinity and selectivity for the human kappa-opioid receptor. The work also introduces a general workflow for identifying structural changes that keep molecular complexity high while reducing synthetic complexity.
The κ-opioid receptor (KOR) is activated by diverse agonists through both shared and distinct molecular mechanisms. By docking four chemically different ligands (dynorphin A, U-69593, salvinorin A, and an octahydroisoquinolinone carboxamide) into the antagonist-bound KOR crystal structure and testing 18 mutated positions, two classes of mutations were identified: those impairing receptor function mainly by reducing ligand binding, and those impairing function without strongly affecting binding. Mutations of the latter type were located at the binding site periphery and did not interact strongly with ligands. These “functional” residues, together with water molecules seen in the crystal structure, likely help transmit the agonist binding signal to conserved rotamer switches that trigger receptor activation.