G protein-coupled receptor drug discovery: implications from the crystal structure of rhodopsin.
G protein-coupled receptors (GPCRs) are a functionally diverse group of membrane proteins that play a critical role in signal transduction. Because of the lack of a high-resolution structure, the heptahelical transmembrane bundle within the N-terminal extracellular and C-terminal intracellular region of these receptors has initially been modeled based on the high-resolution structure of bacterial retinal-binding protein, bacteriorhodopsin. However, the low-resolution structure of rhodopsin, a prototypical GPCR, revealed that there is a minor relationship between GPCRs and bacteriorhodopsins. The high-resolution crystal structure of the rhodopsin ground state and further refinements of the model provide the first structural information about the entire organization of the polypeptide chain and post-translational moieties. These studies provide a structural template for Family 1 GPCRs that has the potential to significantly improve structure-based approaches to GPCR drug discovery.
Ballesteros
J
J
Novasite Pharmaceuticals Inc., 3520 Dunhill Street, San Diego, CA 92121, USA. jballesteros@novasite.com
Palczewski
K
K
D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D019204:GTP-Binding Proteins / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011955:Receptors, Drug / Q000737:chemistry*; D012243:Rhodopsin / Q000737:chemistry*
D011955:Receptors, Drug; D012243:Rhodopsin; D019204:GTP-Binding Proteins