Molecular exploration of the α_1A‐adrenoceptor orthosteric site: Binding site definition for epinephrine, HEAT and prazosin

Abstract

a b s t r a c tDespite the physiological and pharmacological importance of the a 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 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.

The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the α1-adrenoceptor

“…5B). The quinazoline scaffold of non-protonated prazosin was docked close to TM5 to form a hydrogen bond between the 6,7-methoxy groups and SER188 11,12 , a hydrogen bond between the furan oxygen and SER83, and between the prazosin carboxamide and GLN177 side chain; van der Waals interactions with side chains of PHE86, VAL107, ILE178, SER192 11 , PHE289 13 , MET292 and PHE312 12,14 ; π-π interactions with PHE288 and PHE312 12 ; and a π-hydrogen bond interaction with the side chain carboxyl group and backbone peptide carboxamide of ASP106 12,15 . Thus, the proposed binding mode of non-protonated prazosin utilized interactions that were in accord with those described in previous literature.…”

“…Flexible molecular docking simulation was performed using Induced Fit, a part of the Schrödinger Small-Molecule Drug Discovery suite 35 . A binding centroid was defined between residues involved in antagonist binding confirmed by mutagenesis (PHE312, PHE308 and ASP106) and ligands were docked within 15 Å, using an extended sampling protocol without constrains 12,15 . Residues within 5 Å of resulting ligand poses were refined using Prime to improve ligand conformational sampling 36 .…”

Structural and Functional Diversity of Animal Toxins Interacting With GPCRs

“…α1 A AR-D106A was expressed very poorly and binding could be detected only with 125 I-HEAT. ρ-Da1a affinity is affected by this mutation, demonstrating a contribution of this negative charge in the toxin interaction (Maïga et al, 2013a(Maïga et al, , 2014 (Table 2).…”

Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody

“…Orthosteric ligand-binding pocket of α 1A AR Extensive site-directed mutagenesis studies have identified amino acids that form the binding pocket of the α 1A AR, including residues responsible for subtype selectivity [34][35][36][37][38][39][40][41][42] . Our structures largely confirm these observations.…”