Molecular Evolution of Adrenoceptors and Dopamine Receptors:  Implications for the Binding of Catecholamines

Abstract

We derived homology models for all human catecholamine-binding GPCRs (CABRs; the alpha-1, alpha-2, and beta-adrenoceptors and the D1-type and D2-type dopamine receptor) using the bovine rhodopsin-11-cis-retinal X-ray structure. Interactions were predicted from the endogenous ligands norepinephrine or dopamine and from the binding site and were used to optimize receptor-ligand interactions. Similar binding modes in the complexes agree with a large "binding core" conserved across the CABRs, that is, D3.32, V(I)3.33, T3.37, S5.42, S(A/C)5.43, S5.46, F6.51, F6.52, and W6.48. Model structures and docking simulations suggest that extracellular loop 2 could provide a common attachment point for the ligands' beta-hydroxyl via a hydrogen bond donated by the main-chain NH group of residue xl2.52. The modeled CABRs and docking modes are in good agreement with published experimental studies. Complementarity between the ligand and the binding site suggests that the bovine rhodopsin structure is a suitable template for modeling agonist-bound CABRs.

Fluorescence Resonance Energy Transfer Analysis of α2a-Adrenergic Receptor Activation Reveals Distinct Agonist-Specific Conformational Changes

“…This has been proposed for the M 1 muscarinic receptor (Allman et al, 2000), the herpesvirus 8-encoded CXC-chemokine receptor ORF74-HHV8 (Rosenkilde et al, 2006), and specifically for the ␣ 2A -adrenergic receptor (Marjamaki et al, 1999;Nyronen et al, 2001). TMV binds to the catechol OH groups via several serine residues in the ␣ 2A -and the ␤ 2 -adrenergic receptor (Peltonen et al, 2003;Xhaard et al, 2006). This is compatible with our observation that agonists lacking one of the catechol groups fail to induce FRET signals close to TMV (I3-C construct).…”

Structure-Activity Relationships of GPR120 Agonists Based on a Docking Simulation

“…Potential ligand binding sites of GPR120 protein were calculated using the Molegro cavity detection algorithm. The hydrogen bonding energy, which is considered to be one of the important parameters in characterizing the interaction between GPCRs and their ligands (Shim et al, 2003;Xhaard et al, 2006), was estimated in arbitrary units using the Molegro program.…”

Eleven new putative aminergic G-protein coupled receptors from Amphioxus (Branchiostoma floridae): identification, sequence analysis and phylogenetic relationship

“…They also all have a W in extracellular loop I, S 3.39 , W 6.48 and F/Y 6.51 which are also highly conserved in aminergic GPCR's together with the F 5.47 XXP motif (except for YHLP in AmphiAmR8 and YYIP in AmphiAmR10 where there is a conservative substitution of a Y for a F). Additionally, in TMVII the new receptors all contain W 7.40 , N 7.45 and S 7.46 which are also conserved in aminergic GPCR's (Shi and Javitch 2002;Xhaard et al 2006). In addition, in TMVII they also contain the NP 7.50 XXY motif, which is involved in G-protein activation and in interactions with the GTP binding proteins, ARF and Rho.…”

“…Thus, to date in mammalian vertebrates nine subtypes of adrenergic receptor, at least five subtypes of dopamine receptors and fourteen subtypes of 5-hydroxytryptamine receptors have been described. However, in non-mammalian vertebrates, such as fish, the total number of subtypes differs for a given receptor and duplicate receptors have been identified (Xhaard et al 2006). There is considerable interest in the way in which these large numbers of GPCR receptor subtypes for specific biogenic amines, such as the catecholamine dopamine, could have evolved (Vernier et al 1995;Fredricksson et al 2003;Perez 2003;Hauser et al 2006).…”