THE STERIC TRIGGER IN RHODOPSIN ACTIVATION

Rhodopsin is the seven transmembrane helix receptor responsible for di m light vision in vertebrate rod cells. The protein has structural hom ology with the other G protein-coupled receptors, which suggests that the tertiary structures and activation mechanisms are likely to be sim ilar. However, rhodopsin is unique in several respects. The most strik ing is the fact that the receptor ''ligand'', 11-cis retinal, is coval ently bound to the protein and is converted from an ''antagonist'' to an ''agonist'' upon absorption of light. NMR studies of rhodopsin and its primary photoproduct, bathorhodopsin, have generated structural co nstraints that enabled docking of the 11-cis and all-trans retinal chr omophores into a low-resolution model of the protein proposed by Baldw in. These studies also suggest a mechanism for how retinal isomerizati on leads to rhodopsin activation. More recently, mutagenesis studies h ave extended these results by showing how the selectivity of the retin al-binding site can be modified to favor the all-trans over the 11-cis isomer. The structural constraints produced from these studies, when placed in the context of a high-resolution model of the protein, provi de a coherent picture of the activation mechanism, which we show invol ves a direct steric interaction between the retinal chromophore and tr ansmembrane helix 3 in the region of Gly121. (C) 1997 Academic Press L imited.