This study represents the first attempt to couple, by computational experiments, the mechanisms of intramolecular and intermolecular communication concerning a guanidine nucleotide exchange factor (GEF), the thromboxane A2 receptor (TXA2R), and the cognate G protein (Gq) in its heterotrimeric GDP-bound state. Two-way pathways mediate the communication between the receptor-G protein interface and both the agonist binding site of the receptor and the nucleotide binding site of the G protein. The increase in solvent accessibility in the neighborhoods of the highly conserved E/DRY receptor motif, in response to agonist binding, is instrumental in favoring the penetration of the C-terminus of Gqalpha in between the cytosolic ends of H3, H5, and H6. The arginine of the E/DRY motif is predicted to be an important mediator of the intramolecular and intermolecular communication involving the TXA2R. The receptor-G protein interface is predicted to involve multiple regions from the receptor and the G protein alpha-subunit. However, receptor contacts with the C-terminus of the alpha5-helix seem to be the major players in the receptor-catalyzed motion of the alpha-helical domain with respect to the Ras-like domain and in the formation of a nucleotide exit route in between the alphaF-helix and beta6/alpha5 loop of Gqalpha. The inferences from this study are of wide interest, as they are expected to apply to the whole rhodopsin family, given also the considerable G protein promiscuity.

Mechanisms of inter- and intramolecular communication in GPCRs and G proteins / Raimondi, F; Seeber, M; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - ELETTRONICO. - 130:13(2008), pp. 4310-4325. [10.1021/ja077268b]

Mechanisms of inter- and intramolecular communication in GPCRs and G proteins

DE BENEDETTI, Pier Giuseppe;FANELLI, Francesca
2008

Abstract

This study represents the first attempt to couple, by computational experiments, the mechanisms of intramolecular and intermolecular communication concerning a guanidine nucleotide exchange factor (GEF), the thromboxane A2 receptor (TXA2R), and the cognate G protein (Gq) in its heterotrimeric GDP-bound state. Two-way pathways mediate the communication between the receptor-G protein interface and both the agonist binding site of the receptor and the nucleotide binding site of the G protein. The increase in solvent accessibility in the neighborhoods of the highly conserved E/DRY receptor motif, in response to agonist binding, is instrumental in favoring the penetration of the C-terminus of Gqalpha in between the cytosolic ends of H3, H5, and H6. The arginine of the E/DRY motif is predicted to be an important mediator of the intramolecular and intermolecular communication involving the TXA2R. The receptor-G protein interface is predicted to involve multiple regions from the receptor and the G protein alpha-subunit. However, receptor contacts with the C-terminus of the alpha5-helix seem to be the major players in the receptor-catalyzed motion of the alpha-helical domain with respect to the Ras-like domain and in the formation of a nucleotide exit route in between the alphaF-helix and beta6/alpha5 loop of Gqalpha. The inferences from this study are of wide interest, as they are expected to apply to the whole rhodopsin family, given also the considerable G protein promiscuity.
2008
130
13
4310
4325
Mechanisms of inter- and intramolecular communication in GPCRs and G proteins / Raimondi, F; Seeber, M; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca. - In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. - ISSN 0002-7863. - ELETTRONICO. - 130:13(2008), pp. 4310-4325. [10.1021/ja077268b]
Raimondi, F; Seeber, M; DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/612817
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