Opioid Receptor Three-Dimensional Structures from Distance Geometry Calculations with Hydrogen Bonding Constraints

摘要: Abstract Three-dimensional structures of the transmembrane, seven α -helical domains and extracellular loops δ , μ κ opioid receptors, were calculated using distance geometry algorithm, with hydrogen bonding constraints based on previously developed general model transmembrane -bundle for rhodopsin-like G-protein coupled receptors ( Biophys . J 1997. 70:1963). Each receptor structure has an extensive network interhelical bonds a ligand-binding crevice that is partially covered by β -hairpin formed second loop. The binding cavities consist inner "conserved region" composed 18 residues are identical in peripheral "variable region," 19 different subtypes responsible subtype specificity various ligands. Sixteen -, or -selective, conformationally constrained peptide nonpeptide agonists antagonists affinity labels fit into pockets receptors. All ligands considered have similar spatial arrangement tyramine moiety alkaloids Tyr 1 peptides interacting conserved bottom pocket N + OH groups forming ionic interactions H-bonds aspartate from helix III histidine VI, respectively. central, fragments opioids (the disulfide-bridged cycles ring ligands) oriented approximately perpendicular to directed toward surface. results obtained qualitatively consistent ligand affinities, cross-linking studies, mutagenesis data.