title: Molecular exploration of the α(1A)-adrenoceptor orthosteric site: binding site definition for epinephrine, HEAT and prazosin.
abstract: Despite the physiological and pharmacological importance of the α1A-adrenoreceptor, the mode of interactions of classical agonists and radioactive ligands with this receptor is not yet clearly defined. Here, we used mutagenesis studies and binding experiments to evaluate the importance of 11 receptor sites for the binding of (125)I-HEAT, (3)H-prazosin and epinephrine. Only one residue (F312) commonly interacts with the three molecules, and, surprisingly, D106 interacts only with epinephrine in a moderate way. Our docking model shows that prazosin and HEAT are almost superimposed into the orthosteric pocket with their tetralone and quinazoline rings close to the phenyl ring of the agonist.
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France.
authors.forename: Arhamatoulaye
authors.initials: A
authors.lastname: Maïga
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Dupont
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Blanchet
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Marcon
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gilquin
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Servent
authors.affiliation: CEA, iBiTec-S, Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), F-91191 Gif sur Yvette, France. Electronic address: Nicolas.gilles@cea.fr.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gilles
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004837:Epinephrine / Q000378:metabolism*; D062105:Molecular Docking Simulation; D011224:Prazosin / Q000378:metabolism*; D011487:Protein Conformation; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D044024:Tetralones / Q000378:metabolism*
chemical_list: D018340:Receptors, Adrenergic, alpha-1; D044024:Tetralones; C048008:2-(beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl)tetralone; D011224:Prazosin; D004837:Epinephrine
keywords: Adrenoceptor; Binding study; Epinephrine; HEAT; Orthosteric site; Prazosin