Projection structure of rhodopsin

Abstract

Light absorption by the visual pigment rhodopsin triggers, through G-protein coupling, a cascade of events in the outer segment of the rod cell of the vertebrate retina that results in membrane hyperpolarization and nerve excitation. Rhodopsin, which contains 348 amino acids, has seven helices that cross the disk membrane and its amino terminus is extracellular. A wealth of biochemical data is available for rhodopsin: 11-cis retinal is bound to lysine 296 in helix VII; glutamic acid 113 on helix III is the counterion to the protonated Schiff's base; a disulphide bridge, cystine 110-187, connects helix III to the second extracellular loop e2 (refs 13, 14); the carboxy terminus has two palmitoylated cysteines forming a cytoplasmic loop i4 (ref. 15); three intracellular loops i2, i3 and i4 mediate activation of the heterotrimeric G protein transducin; glutamic acid 135 and arginine 136 at the cytoplasmic end of helix III affect binding of transducin. But to provide a framework to interpret these data, not only for rhodopsin but for other G-protein-coupled receptors, requires the structure to be determined. Here we present a projection map of rhodopsin showing the configuration of the helices.

Site-directed mutagenesis of the human adenosine A2A receptor. Critical involvement of Glu13 in agonist recognition

“…It has to be kept in mind that there is virtually no sequence homology between this bacterial proton pump and G-protein-coupled receptors. Its mammalian homolog rhodopsin, however, is a G-protein-coupled receptor, and its overall structure has been elucidated too (Schertler et al, 1993). Its appearance is that of bacteriorhodopsin, although the helices might be more tilted relative to each other.…”

Synthesis and Evaluation of Bivalent NDP-α-MSH(7) Peptide Ligands for Binding to the Human Melanocortin Receptor 4 (hMC4R)

“…As a proof of the concept that such cell surface proteins can indeed be targeted specifically, we chose to mimic the cancer cells through overexpression of MC4 receptors because of our considerable experience with MC4 receptors (2,3). Thus, in order to demonstrate that multivalent peptide ligands bind to their target receptors with increased affinity and cooperativity, we have constructed ligands containing two copies of MSH (7), 1 7 ]-α-melanocyte stimulating hormone (NDP-α-MSH) (2), a peptide hormone analogue that binds specifically to the melanocortin receptors. These two MSH (7) ligands are separated by a linker, which is constructed with different amino acids and/or organic derivatives in order to provide differences in flexibility and length.…”

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

“…Despite the large number of GPCRs, for many years direct structural information was available only for bovine rhodopsin, mainly through the 2D projection map disclosed by Schertler and coworkers in 1993 and the three-dimensional (3D) crystal structure solved for the first time by Palczewski and coworkers in 2000 [3,4]. Thus, structure-function studies of GPCRs relied heavily on sequence and phylogenetic analyses, rhodopsin-based homology modeling, and docking studies supported by site-directed mutagenesis and ligand structure-activity relationships (SAR) data [5,6].…”