title: A 3D model of the delta opioid receptor and ligand-receptor complexes.
abstract: A model for the 3D structure of the transmembrane domain of the delta opioid receptor was predicted from the sequence divergence analysis of 42 sequences of G-protein coupled peptide hormone receptors belonging to the opioid, somatostatin and angiotensin receptor families. No template was used in the prediction steps, which include multiple sequence alignment, calculation of a variability profile of the aligned sequences, use of the variability profile to identify the boundaries of transmembrane regions, prediction of their secondary structure, optimization of the packing shape in a helix bundle, prediction of side chain conformations and structural refinement. The general shape of the model is similar to that of the low resolution rhodopsin structure in that the TM3 and TM7 helices are most buried in the bundle and the TM1 and TM4 helices are most exposed to the lipid phase. An initial assessment of this model was made by determining to what extent a binding site identified using four structurally disparate high affinity delta opioid ligands was consistent with known mutational studies. With the assumption that the protonated amine nitrogen, a feature common to all delta opioid ligands, interacts with the highly conserved Asp127 in TM3, a pocket was found that satisfied the criteria of complementarity to the requirements for receptor recognition for these four diverse ligands, two delta selective antagonists (the fused ring naltrindole and the peptide Tyr-Tic-Phe-Phe-NH2) and the two agonists lofentanil and BW373U86 deduced from previous studies of the ligands alone. These ligands could be accommodated in a similar region of the receptor. The receptor binding site identified in the optimized complexes contained many residues in positions known to affect ligand binding in G-protein coupled receptors. These results also allowed identification of key residues as candidates for point mutations for further assessment and refinement of this model as well as preliminary indications of the requirements for recognition of this receptor.
authors.affiliation: Molecular Research Institute, Palo Alto, CA 94304, USA.
authors.forename: I
authors.initials: I
authors.lastname: Alkorta
authors.forename: G H
authors.initials: GH
authors.lastname: Loew
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D005075:Biological Evolution; D003198:Computer Simulation; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011945:Receptors, Angiotensin / Q000737:chemistry; D011957:Receptors, Opioid / Q000737:chemistry; D017465:Receptors, Opioid, delta / Q000737:chemistry* / Q000378:metabolism; D018000:Receptors, Peptide / Q000145:classification; D017481:Receptors, Somatostatin / Q000737:chemistry; D017421:Sequence Analysis / Q000379:methods*
chemical_list: D008024:Ligands; D011945:Receptors, Angiotensin; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D018000:Receptors, Peptide; D017481:Receptors, Somatostatin