Molecular Dynamics Simulations of the Ligand-Induced Chemical Information Transfer in the 5-HT_1A Receptor

Abstract

Comparative molecular dynamics simulations of the 5-HT(1A) receptor in its empty as well as agonist- (i.e. active) and antagonist-bound (i.e. nonactive) forms have been carried out. The agonists 5-HT and (R)-8-OH-DPAT as well as the antagonist WAY100635 have been employed. The results of this study strengthen the hypothesis that the receptor portions close to the E/DRY/W motif, with prominence to the cytosolic extensions of helices 3 and 6, are particularly susceptible to undergo structural modification in response to agonist binding. Despite the differences in the structural/dynamics behavior of the two agonists when docked into the 5-HT(1A) receptor, they both exert a destabilization of the intrahelical and interhelical interactions found in the empty and antagonist-bound receptor forms between the arginine of the E/DRY sequence and both D133(3.49) and E340(6.30). For both agonists, the chemical information transfer from the extracellular to the cytosolic domains is mediated by a cluster of aromatic amino acids in helix 6, following the ligand interaction with selected amino acids in the extracellular half of the receptor, such as D116(3.32), S199(5.42), Y195(5.38), and F361(6.51). A significant reduction in the bend at P360(6.50), as compared to the empty and the antagonist-bound receptor forms, is one of the features of the agonist-bound forms that is related to the breakage of the interhelical salt bridge between the E/DRY arginine and E340(6.30). Another structural feature, shared by the agonist-bound receptor forms and not by the empty and antagonist-bound forms, is the detachment of helices 2 and 4, as marked by the movement of W161(4.50) away from helix 2, toward the membrane space.

Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling

“…These interactions are released in the structures of the highly active a 1b -AR mutants, suggesting that both the two anionic amino acids stabilize the inactive state of the receptor. The role of the charge-reinforced H-bond between R3.50 and E6.30 in maintaining the inactive states of GPCRs has been overemphasized by a number of computational and in vitro experiments [23,24,[28][29][30][45][46][47][48][49]. However, the significantly lower conservation of the glutamate/aspartate at position 6.30 (i.e., 32%) compared to the glutamate/aspartate at 3.49 (i.e., 86%) [50] makes its potential role valid only for a very limited number of GPCRs.…”

“…Structural features of ligand-induced active and non-active states Over the last 10 years, we have done extensive studies aimed at investigating the propagation of the structural modifications from the ligand binding site to distal receptor domains, following the docking of selected agonists and antagonists into their cognate receptors [31,35,42,43,48,52,53]. Targets of our study have been different members of family A, including a 1b -AR, m3-muscarinic receptor, OTR, 5-HT 1A serotonin receptor, MCHR1, and MCHR2 [31,35,42,43,48,52,53].…”

“…Targets of our study have been different members of family A, including a 1b -AR, m3-muscarinic receptor, OTR, 5-HT 1A serotonin receptor, MCHR1, and MCHR2 [31,35,42,43,48,52,53].…”

“…These configurations differ from those of the empty receptor forms. On the other hand, comparing a large number of average configurations obtained for the different agonist-and antagonist-receptor complexes following different computational protocols, it was possible to infer similarities in the interaction modes of the different agonists at their cognate receptors [31,48,52]. The receptor sites, in which most of such similarities occur, essentially concern selected positions in the extracellular halves of H3, H5, and H6.…”

“…The receptor sites, in which most of such similarities occur, essentially concern selected positions in the extracellular halves of H3, H5, and H6. Computational modeling of the agonist-bound forms of the 5-HT 1A , MCH, and OT receptors suggests that these receptor portions hold the key contact points for the ligand moieties responsible for the efficacy [31,48,52]. According to extensive computational analyses, hallmarks of the ligand-induced active and non-active forms of the receptors were found to involve R3.50, the arginine of the E/ DRY motif, and the cytosolic extensions of H3 and H6.…”