3-DIMENSIONAL MODELS OF THE D1-DOPAMINE AND D2-DOPAMINE RECEPTORS

The G protein-linked receptors are a ubiquitous family of membrane-bou nd receptors that bind ligands ranging from small molecules to peptide s and proteins. The function of these receptors is to convey informati on on the concentration of extracellular ligands to the inside of the cell and activate specific intracellular biochemical pathways. Three-d imensional models of the dopamine D1 and D2 receptors have been develo ped based on the primary sequence similarities, site-directed mutagene sis data and ligand structure-activity relationships of a number of th ese receptors. The agonist and antagonist binding sites are suggested to be in the region between helices II, III, VI and VII. This receptor model can be used to explain the structure-activity data of dopamine agonists and antagonists and to aid in the design of new analogs. A mo lecular mechanism for triggering the start of the receptor activation process based on agonist interaction with the conserved aspartic acid on helix II is proposed. This aids in our understanding of the structu ral requirements for agonist function. This receptor model has been us ed to develop models of other receptors and to rationalize the structu re-activity data of peptide and peptidomimetic ligands.