PUBLICATION
Exploring the unique pharmacology of a novel opioid receptor, ZFOR1, using molecular modeling and the 'message-address' concept
- Authors
- McFadyen, I.J., Metzger, T.G., Paterlini, M.G. and Ferguson, D.M.
- ID
- ZDB-PUB-020906-2
- Date
- 2001
- Source
- Protein engineering 14(12): 953-960 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Binding Sites
- Ligands
- Models, Molecular
- Molecular Sequence Data
- Protein Structure, Tertiary
- Receptors, Opioid, delta/chemistry*
- Receptors, Opioid, delta/drug effects
- Receptors, Opioid, delta/metabolism
- Sequence Analysis, Protein
- Zebrafish
- Zebrafish Proteins/chemistry*
- Zebrafish Proteins/drug effects
- Zebrafish Proteins/metabolism
- PubMed
- 11809925 Full text @ Protein Eng.
Citation
McFadyen, I.J., Metzger, T.G., Paterlini, M.G. and Ferguson, D.M. (2001) Exploring the unique pharmacology of a novel opioid receptor, ZFOR1, using molecular modeling and the 'message-address' concept. Protein engineering. 14(12):953-960.
Abstract
Previous studies have probed the structural basis of ligand selectivity in the mu, delta and kappa opioid receptors through the application of molecular modeling techniques in concert with the 'message-address' concept. Here, this approach was used in an attempt to rationalize the unique pharmacological profile of a recently cloned novel opioid receptor, ZFOR1 (ZebraFish Opioid Receptor 1). Specifically, a model of the transmembrane domains of ZFOR1 was constructed and used to explore the binding modes of various prototypical opioid ligands. The results show that the 'message' portion of the binding pocket of ZFOR1 is highly conserved; hence, the binding modes of non-selective opioid ligands are well preserved. In contrast, a small number of variant residues at the extracellular end of the binding pocket, particularly Lys288 (VI:26) and Trp304 (VII:03), are shown to create adverse steric interactions with all delta and kappa selective ligands examined, thereby disrupting their binding modes. These results are consistent with, and serve as an explanation for, the observed pharmacology of this receptor, lending support to both the validity of the 'message-address' concept itself and to the use of molecular modeling approaches in its application.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping