Structure and activation of rhodopsin

Abstract

Rhodopsin is the first G-protein-coupled receptor (GPCR) with its three-dimensional structure solved by X-ray crystallography. The crystal structure of rhodopsin has revealed the molecular mechanism of photoreception and signal transduction in the visual system. Although several other GPCR crystal structures have been reported over the past few years, the rhodopsin structure remains an important model for understanding the structural and functional characteristics of other GPCRs. This review summarizes the structural features, the photoactivation, and the G protein signal transduction of rhodopsin.

Figure 1

Overall structure of ground sate bovine rhodopsin and its key features (PDB: 1F88). (A) The seven-transmembrane helix domain with the retinal in gray stick and the ligand binding pocket shown as a pink mesh. Major ligand binding residues around the ligand binding pocket are shown as yellow sticks and are labeled. Other features include the ionic lock (yellow sticks) and the NPXXY motif (orange). (B) Two-dimensional sequence of bovine rhodopsin with the starting and ending residues of secondary structural elements indicated. The disulfide bond connecting EL2 to helix 3 is shown in orange. N, amino terminus; C, carboxyl terminus; EL, extracellular loop; CL, cytoplasmic loop. (C) The ligand binding pocket (pink mesh) of rhodopsin with EL2 (the lid of the pocket) shown in dark brown. The disulfide bond between C110 and C187 is labeled.

Figure 2

Ligand binding and conformational changes in rhodopsin. (A) Chemical structures of 11-cis- and all-trans-retinal. (B) 11-cis-retinal (in gray) in the ligand binding pocket is associated with the surrounding residues of the protein moiety (green, PDB: 1F88). (C) Conformational changes in retinal and the protein moiety of rhodopsin upon photoactivation. The photoactivated all-trans-retinal (PDB: 3PQR) is magenta and the ground-state 11-cis-retinal (PDB: 1F88, gray) is superposed on the activated all-trans-retinal for comparison. The protein moiety of activated rhodopsin (PDB: 3PQR) is dark brown. (D) The key conformational changes in rhodopsin upon photoactivation are the outward tilting of the cytoplasmic end of helix 6 (indicated by the horizontal arrow), creating a crevice for G-protein binding, and the elongation of the cytoplasmic end of helix 5 (indicated by the vertical arrow) that provides more interface for G-protein interaction. Green shows the ground-state conformation (PDB: 1F88), and brown shows the activated conformation (PDB: 3PQR). (E) Bottom view of panel D.

Figure 3

Rhodopsin-G protein interface. (A) Rhodopsin in complex with a synthetic peptide derived from helix α5 of the Gα subunit of transducin (PDB: 3PQR). The rhodopsin residues interacting with the Gα peptide are labeled. (B) Comparison of the binding mode of rhodopsin with the synthetic peptide and that of the β2-adrenergic receptor with intact G protein (PDB: 3SN6). The β2-adrenergic receptor is blue and the Gα subunit is cyan. For clarity, only helix α5 of the Gα subunit is shown. (C) The whole-complex model of the β2-adrenergic receptor with intact G protein (PDB: 3SN6). The β2-adrenergic receptor is blue, the Gα subunit is cyan, the Gβ subunit is brown, and the Gγ subunit is pink. RN, N-terminus of the receptor; RC, C-terminus of the receptor; αN, N-terminus of the Gα subunit; αC, C-terminus of the Gα subunit; βN, N-terminus of the Gβ subunit; βC, C-terminus of the Gβ subunit; γN, N-terminus of the Gγ subunit; γC, C-terminus of the Gγ subunit.

Figure 4

A comparison of the ligand-induced activation modes of GPCRs and nuclear receptors. (A) Ligand-induced rearrangement of the C-terminal AF2 helix and coactivator recruitment of a peroxisome proliferator-activated receptor ligand binding domain (PPAR LBD). At left is an apo PPAR LBD (PDB: 1PRG); middle, the LBD upon the ligand binding-induced conformational change in the AF2 helix and the formation of the coactivator binding site (PDB: 1I7G); at right, the LBD upon the subsequent coactivator recruitment (PDB: 1K7L). The LBD core structure is cyan; the AF2 helix, green; and the coactivator motif, brown. (B) Cartoon presentation showing that ligand activation induces conformational changes in the core domain of GPCRs but not in that of NRs. Blue are the core domains of both receptors; Red are the ligands; Orange are the G protein binding to the GPCR and the coactivator binding to the NR.