Structure-activity relationships for transmembrane signaling: the receptor's turn.
The cloning, sequencing, and functional expression in host cells of a variety of receptors has led to a focus on the structural determinants of pharmacologic receptors involved in the complex processes of ligand binding and cell activation. The three basic mechanisms of receptor-mediated transmembrane signaling (ligand-regulated ion flux; ligand-regulated receptor-enzymes; ligand-regulated receptor-G protein activation) can now be placed in the structural context of at least three receptor superfamilies: 1) ligand-regulated oligomeric ion channels, 2) ligand-regulated tyrosine kinases, and 3) G protein-linked rhodopsin-related receptors. For each of these receptor superfamilies, structure-activity studies that use 1) site-directed mutagenesis, 2) cassette switching to form receptor chimeras, and 3) sequence-specific antireceptor antibodies are beginning to delineate the domains responsible for specific receptor functions. Analyses of such receptor domains related to: 1) ligand binding, 2) membrane insertion, 3) catalytic activity (in the case of receptor-enzymes), 4) internalization and interaction with other membrane constituents, 5) substrate or G protein binding, and 6) regulatory sites of receptor phosphorylation are discussed, using as principal examples the nicotinic receptor for acetylcholine, the epidermal growth factor-urogastrone receptor, and the beta-adrenergic receptor. These studies illustrate that in terms of structure-activity studies, which have traditionally emphasized the ligand, it is now the receptor's turn for intense attention.
Hollenberg
M D
MD
Department of Pharmacology and Therapeutics, University of Calgary, Faculty of Medicine, Alberta, Canada.
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D008024:Ligands; D008560:Membrane Fluidity; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D008024:Ligands; D011956:Receptors, Cell Surface; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins