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Molecular exploration of the α 1A ‐adrenoceptor orthosteric site: Binding site definition for epinephrine, HEAT and prazosin
Author(s) -
Maïga Arhamatoulaye,
Dupont Mélanie,
Blanchet Guillaume,
Marcon Elodie,
Gilquin Bernard,
Servent Denis,
Gilles Nicolas
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.10.033
Subject(s) - prazosin , chemistry , binding site , epinephrine , agonist , stereochemistry , docking (animal) , antagonist , pharmacology , receptor , biochemistry , endocrinology , biology , medicine , nursing
Despite the physiological and pharmacological importance of the α 1A ‐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.