Comparative molecular dynamics simulations of the 5-HT1A 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-HT1A 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 61 following the ligand interaction with selected amino acids in the extracellular half of the receptor, such as D 116(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.

Molecular dynamics simulations of the ligand-induced chemical information transfer in the 5-HT1A receptor / M., Seeber; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca. - In: JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES. - ISSN 0095-2338. - ELETTRONICO. - 43(2003), pp. 1520-1531. [10.1021/ci034069c]

Molecular dynamics simulations of the ligand-induced chemical information transfer in the 5-HT1A receptor

DE BENEDETTI, Pier Giuseppe;FANELLI, Francesca
2003

Abstract

Comparative molecular dynamics simulations of the 5-HT1A 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-HT1A 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 61 following the ligand interaction with selected amino acids in the extracellular half of the receptor, such as D 116(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.
43
1520
1531
Molecular dynamics simulations of the ligand-induced chemical information transfer in the 5-HT1A receptor / M., Seeber; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca. - In: JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES. - ISSN 0095-2338. - ELETTRONICO. - 43(2003), pp. 1520-1531. [10.1021/ci034069c]
M., Seeber; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/307884
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