On the structure and activity of membrane receptors: A computational simulation of ligand-triggered activation in a model 5-HT<inf>1A</inf> receptor

The relation between receptor structure and the mechanism by which ligands with different pharmacological efficacy elicit a response is analyzed in a three-dimensional molecular model of the human 5-HT1A receptor [Pardo et al., J. Biomed. Sci. 3, 98 (1996)]. According to the model, the main interaction of the endogenous neurotransmitter serotonin (5-HT) to the human 5-HT1A receptor consists of (i) the ionic interaction between the protonated side-chain amine of 5-HT and the conserved Asp-116, located in transmembrane helix (TMH) 3; (ii) the hydrogen bond between the 5-OH group of 5-HT and Thr-199, located in TMH 5; and (iii) the complex between the aromatic indole ring of 5-HT and His-192, located in TMH 5. Ab initio quantum chemical calculations were used to position ligands in molecular models of the binding pocket of the 5-HT1A receptor consisting of these interacting residues. The consequences of the interactions between the ligands and the proposed recognition sites of the 5-HT1A receptor, reflected in the electronic structure of the complexes, suggest a mechanism by which the receptor activation is triggered by ligand binding. Results from the computations show a more favorable interaction of the aromatic ring of 5-HT (or of the 5-HT1A selective agonist 8-OH DPAT) with the protonated form of His-192 than with the neutral form. The change in the reactivity of the imidazole ring then leads to the attraction of a proton from another site in the receptor: Arg-175 in TMH 4. This proton transfer to His-192 that is triggered by the interaction with ligand is facilitated by Asp-191 in TMH 5, as shown by energetic considerations. The position of the ligand recognition pocket in the transmembrane bundle of the 5-HT1A receptor suggests that the ligand-induced proton transfer may cause a conformational change in the tertiary structure of the receptor that could be transmitted toward the intracellular end to facilitate the transmission of the signal. ©1997 John Wiley & Sons, Inc.