Structure of serotonin receptors: molecular underpinning of receptor activation and modulation
Markus Zweckstetter, Alexander Dityatev, Evgeni Ponimaskin
Abstract
The structural basis of the regulation of serotonin (5-hydroxytryptamine, 5-HT) receptors by ligands and lipids is only emerging. A recent study by Xu and colleagues 1 published in Nature addresses this issue by resolving five structures of 5-HT 1 receptor-G protein complexes. These include 5-HT 1A in the apostate, i.e. not bound to a ligand, 5-HT 1A and 5-HT 1D bound to serotonin or the atypical antipsychotic aripiprazole (for 5-HT 1A ), and 5-HT 1E bound to its selective agonist BRL-54443. These highresolution structures and their comparison enable critical insights into the conformational basis of basal and ligand activation of 5-HT 1 receptors, the pan-agonism of serotonin, and the mechanisms for modulation of 5-HT 1 receptors by lipids. Besides, the structural analysis reveals important determinants for ligand selectivity and drug recognition by 5-HT 1 receptors (Fig.