title: Theoretical study of the electrostatically driven step of receptor-G protein recognition.
abstract: This study proposes a theoretical model describing the electrostatically driven step of the alpha 1 b-adrenergic receptor (AR)-G protein recognition. The comparative analysis of the structural-dynamics features of functionally different receptor forms, i.e., the wild type (ground state) and its constitutively active mutants D142A and A293E, was instrumental to gain insight on the receptor-G protein electrostatic and steric complementarity. Rigid body docking simulations between the different forms of the alpha 1 b-AR and the heterotrimeric G alpha q, G alpha s, G alpha i1, and G alpha t suggest that the cytosolic crevice shared by the active receptor and including the second and the third intracellular loops as well as the cytosolic extension of helices 5 and 6, represents the receptor surface with docking complementarity with the G protein. On the other hand, the G protein solvent-exposed portions that recognize the intracellular loops of the activated receptors are the N-terminal portion of alpha 3, alpha G, the alpha G/alpha 4 loop, alpha 4, the alpha 4/beta 6 loop, alpha 5, and the C-terminus. Docking simulations suggest that the two constitutively active mutants D142A and A293E recognize different G proteins with similar selectivity orders, i.e., G alpha q approximately equal to G alpha s > G alpha i >> G alpha t. The theoretical models herein proposed might provide useful suggestions for new experiments aiming at exploring the receptor-G protein interface.
authors.affiliation: Dipartimento di Chimica, Università di Modena e Reppio Emilia, Modena, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fanelli
authors.forename: C
authors.initials: C
authors.lastname: Menziani
authors.forename: A
authors.initials: A
authors.lastname: Scheer
authors.forename: S
authors.initials: S
authors.lastname: Cotecchia
authors.forename: P G
authors.initials: PG
authors.lastname: De Benedetti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D019204:GTP-Binding Proteins / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry*; D016415:Sequence Alignment; D055672:Static Electricity
chemical_list: D018340:Receptors, Adrenergic, alpha-1; D019204:GTP-Binding Proteins