A Two Model Receptor System of the Alpha_1DAdrenergic Receptor To Describe Interactions with Epinephrine and BMY7378

Abstract

In this study, we have developed a two receptor model system to describe the R and R states of G-protein coupled receptors, specifically the alpha(1D) adrenergic receptor. The two models interact with agonist (epinephrine) and antagonist (BMY7378) differently. The active model has increased interactions with epinephrine. The inactive model has increased interactions with BMY7378. We also explored the protonation state of the ligands. When the most basic amine was protonated, we found increased hydrogen bonding and increased aromatic interactions. Protonated epinephrine hydrogen bonds with Asp176 and has aromatic residues Trp172, Trp235, Trp361, and Phe388 within 3 Angstroms. Protonated BMY7378 hydrogen bonds with Trp172 and Lys236 and has aromatic residues Trp172, Trp254, Phe364, Phe384, and Phe388 within 3 Angstroms. We conclude that the two model system is required to represent the two states of the receptor and that protonation of the ligand is also critical.

High Vascular Tone of Mouse Femoral Arteries In Vivo Is Determined by Sympathetic Nerve Activity Via α1A- and α1D-Adrenoceptor Subtypes

“…We have shown previously that systemic effects are avoided through the use of this approach [25], [26]. In this study we determined the functional contributions of α 1 -adrenoceptor subtype to femoral artery tone in vivo by using the α 1 -adrenoceptor selective antagonist prazosin [27], the α 1A -adrenoceptor selective antagonist RS100329 [28], the α 1D -adrenoceptor selective antagonist BMY7378 [29], [30] and the preferential α 1B -adrenoceptor alkylating agent, chloroethylclonidine [31].…”

Two Model System of the α1A-Adrenoceptor Docked with Selected Ligands

“…Two homology models were developed for the R 1A human sequence as in our previously published work. 16 The active model used the S1P 1 model as a template, and the inactive model used the crystal structure of bovine rhodopsin as a template. Each model was minimized to a root-mean-square gradient (RMSG) of 0.1 kcal/mol A to prevent collapse of the pocket within the helical bundle using the AMBER94 force field.…”

“…Homology modeling affords the opportunity to develop in silico models of difficult to crystallize proteins. We have developed two homology models for the R 1D receptor 16 to represent the active and inactive conformations. Two models are needed since the receptor changes conformation when binding with agonists or antagonists.…”

GPCR Conformations: Implications for Rational Drug Design

“…Homology modeling studies have used a variety of template structures including bacteriorhodopsin [158,159], the theoretical model developed by Pogozheva (PDB ID: 1BOJ [152]) [160-162], the bovine rhodopsin crystal structure published in 2000 (PDB ID 1F88 [93]) [61,163-169], the rhodopsin structure published in 2004 (PDB ID 1GZM [98]) [170], and the crystal structure of the β2 aderenoceptor (PDB ID: 2R4R [33]) [171-173]. Recently groups have begun to address the issue of quaternary structure within the lipid bilayer [61] or homo or heterodimers [174,175].…”

“…Overall, the predicted hydrogen bonding networks show impressive correlation with the crystal structure given the low-resolution experimental information that provided only helical tilts and packing geometries. Many groups have used this model as a template to develop homology models of various GPCRs [152,161,163,189-195] The validity that these systems have had in predicting agonist receptor interactions suggests that this template is still suitable to develop models for the active state of class A GPCR.…”