An Analysis of the Conserved Residues between Halobacterial Retinal Proteins and G-Protein Coupled Receptors:  Implications for GPCR Modeling

Abstract

An alignment of the transmembrane domains of halobacterial retinal proteins (including bacteriorhodopsin) and G-protein coupled receptors (GPCRs) is presented based on the commonality of conserved residues between families. Due to the limited sequence homology displayed by these proteins, an alternative strategy is proposed for sequence alignment that correlates residues within secondary structure elements. The nonsequential alignment developed identifies three proline and two aspartates residues that share common positions and, in the former case, similar functions in the transmembrane domain. The alignment is further applied to model the packing of transmembrane helices 5 and 6 of the beta-adrenergic receptor based on the backbone coordinates of bacteriorhodopsin helices 3 and 2, respectively. Unlike models derived from standard sequential alignments, the approach developed here allows the key structural features conferred by the proline residues to be captured during model building. The structure described is also compared with available site directed mutagenesis results as well as existing GPCR models. In addition to the implications to model building, the commonality observed suggests a potential relationship among the GPCRs and retinal proteins.

G-Protein Coupled Receptors: Models, Mutagenesis, and Drug Design

“…60 In both her models, she incorporated an analysis of interhelical loop lengths and analyses of residue conservation, variability, and polarity. Among her conclusions, she demonstrated that the helices almost certainly had to be arranged adjacent to each other; atypical arrangements such as those by Pardo 61 and Metzger et al 62 are shown to be fairly unlikely. Furthermore, although her analysis was consistent with either a clockwise or counterclockwise arrangement of helices, she determined that the latter was more likely.…”

Molecular Simulation of Dynorphin A-(1−10) Binding to Extracellular Loop 2 of the κ-Opioid Receptor. A Model for Receptor Activation

“…Computations were performed using a constant dielectric of 4 with a nonbonded cutoff distance of 8.0 Å. The initial coordinates of the TM region of the κ-receptor were taken from a model previously developed in our group to rationalize the binding of naltrexone-based ligands. , This model is unique in that secondary structures are taken from nonsequential alignments to the helical domains of bacteriorhodopsin (BR) …”

“…The initial coordinates of the TM region of the κ-receptor were taken from a model previously developed in our group to rationalize the binding of naltrexone-based ligands. 2,21 This model is unique in that secondary structures are taken from nonsequential alignments to the helical domains of bacteriorhodopsin (BR). 21 This allows the conformational effects of the conserved prolines to be retained in the opioid model which is not possible through direct sequence alignment to BR.…”

Mutational analysis of the structure and function of opioid receptors

“…48 When these four residues are engineered FIGURE 2 Ribbon picture of the transmembrane domains of the GPCRs. The generation of the ribbon model of the GPCR and the coordinate used are described in Metzger et al 138 into the opioid receptor, the resultant opioid receptor mutant can bind DAMGO with high affinity and can efficiently inhibit adenylyl cyclase in response to the agonist. The same mutant did not exhibit high affinity for other opioid receptor peptidic ligands such as dermorphin, CTOP, or Met 5 -enkephalin, or nonpeptidic ligands such as morphine, methadone, or fentanyl.…”