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On the structure and activity of membrane receptors: A computational simulation of ligand‐triggered activation in a model 5‐HT 1A receptor
Author(s) -
Pardo Leonardo,
Weinstein Harel
Publication year - 1997
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/(sici)1097-461x(1997)63:3<767::aid-qua17>3.0.co;2-1
Subject(s) - chemistry , stereochemistry , receptor , 5 ht1a receptor , hydrogen bond , agonist , transmembrane domain , ligand (biochemistry) , protonation , 5 ht receptor , indole test , ring (chemistry) , molecular dynamics , serotonin , molecule , computational chemistry , biochemistry , ion , organic chemistry
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‐HT 1A 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‐HT 1A 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‐HT 1A receptor consisting of these interacting residues. The consequences of the interactions between the ligands and the proposed recognition sites of the 5‐HT 1A 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‐HT 1A 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‐HT 1A 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.