Application of the message-address concept to the docking of naltrexone and selective naltrexone-derived opioid antagonists into opioid receptor models

A binding site model for the opioid family of G-protein coupled receptors (GPCRs) is proposed based on the message-address concept of ligand recognition. Using ligand docking studies of the universal opioid antagonist, naltrexone, the structural basis for "message' recognition is explored...

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Bibliographic Details
Published in:Neurochemical research 1996-11, Vol.21 (11), p.1287-1294
Main Authors: METZGER, T. G, GERMANA PATERLINI, M, PORTOGHESE, P. S, FERGUSON, D. M
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Binding Sites
Biological and medical sciences
Cell receptors
Cell structures and functions
Conserved Sequence
Fundamental and applied biological sciences. Psychology
GTP-Binding Proteins - metabolism
Models, Molecular
Models, Structural
Molecular and cellular biology
Molecular Conformation
Molecular Sequence Data
Naltrexone - analogs & derivatives
Naltrexone - chemistry
Naltrexone - metabolism
Narcotic Antagonists - chemistry
Narcotic Antagonists - metabolism
Neuropeptide receptors
Protein Conformation
Receptors, Opioid, delta - chemistry
Receptors, Opioid, delta - metabolism
Receptors, Opioid, kappa - chemistry
Receptors, Opioid, kappa - metabolism
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Summary:A binding site model for the opioid family of G-protein coupled receptors (GPCRs) is proposed based on the message-address concept of ligand recognition. Using ligand docking studies of the universal opioid antagonist, naltrexone, the structural basis for "message' recognition is explored across all three receptor types, mu, delta, and kappa. The binding mode proposed and basis for selectivity are also rationalized using the naltrexone-derived ligands, naltrindole (NTI) and norbinaltorphimine (nor BNI). These ligands are docked to the receptor according to the common naltrexone core or message. The resulting orientation places key "address' elements in close proximity to amino acid residues critical to selectivity among receptors types. Selectivity is explained by sequence differences in the mu, delta, and kappa receptors at these recognition points. Support for the model is derived from site directed mutagenesis studies and ligand binding data for the opioid receptors and other related GPCRs.
ISSN:0364-3190
1573-6903
DOI:10.1007/BF02532369