Yuan, S*, Peng, Q, Palczewski, K., Vogel, H, Filipek, S*. (2016) Mechanistic Studies on the Stereoselectivity of the Serotonin 5-HT1A Receptor. Angew. Chem. Int. Ed DOI: 10.1002/anie.201603766R1 (2016)

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G-protein-coupled receptors (GPCRs) are involved in a wide range of physiological processes, and they have attracted considerable attention as important targets for developing new medicines. A central and largely unresolved question in drug discovery, which is especially relevant to GPCRs, concerns ligand selectivity: Why do certain molecules act as activators (agonists) whereas others, with nearly identical structures, act as blockers (antagonists) of GPCRs? To address this question, we employed all-atom, long-timescale molecular dynamics simulations to investigate how two diastereomers (epimers) of dihydrofuroaporphine bind to the serotonin 5-HT1A receptor and exert opposite effects. By using molecular interaction fingerprints, we discovered that the agonist could mobilize nearby amino acid residues to act as molecular switches for the formation of a continuous water channel. In contrast, the antagonist epimer remained firmly stabilized in the binding pocket.

Schematic representation of ligand interactions and water influx in the binding site of the 5-HT1A receptor (transmembrane cross-section). Left: agonist isomer (yellow); right: antagonist isomer (cyan). The methyl group at the chiral carbon atom of the ligand is shown in green (partially hidden behind the rest of the molecule in the antagonist). The back part of the 5-HT1A receptor is represented in gray, and the location of the lipid bilayer is indicated by horizontal dotted lines. The central amino acid side chains F6.52 and W6.48 (green), together with the 3–7 lock (residues D3.38 and Y7.43), act as a gate, which after binding of the agonist undergoes a rotational switch (black arrows, left) to form a continuous water channel inside the receptor. Water molecules are depicted as bright yellow spheres, and red arrows (left) indicate the movement of water molecules after opening of the water channel inside the receptor.