Differential helical orientations among related G protein-coupled receptors provide a novel mechanism for selectivity. Studies with salvinorin A and the kappa-opioid receptor.
Timothy A Vortherms, Philip D Mosier, Richard B Westkaemper, Bryan L. Roth
Journal of Biological Chemistry February 2, 2007 DOI: 10.1074/jbc.M609264200 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study using chimeric receptors, site-directed mutagenesis, substituted cysteine accessibility method, and molecular modeling Peer reviewed |
|---|---|
| Topics | Salvia divinorum |
| Keywords | Drug selectivity Mechanism of action Pharmacology Ligand binding Receptor targeting Drug potency Compound selectivity Drug specificity Receptor structure Protein structure Molecular conformation Helical arrangement Molecular mechanism Protein dynamics Structural biology Kappa-opioid receptor Opioid receptors Brain receptors Salvinorin a target Receptor biology Hallucinogen Psychoactive compound Drug compound |
| Citations | 40 |
| Key findings | Differences in the helical orientation of helix 2, influenced by residues Val-108 and Val-118, are critical for the selective binding of salvinorin A to the kappa-opioid receptor. |
Abstract
Salvinorin A, the active component of the hallucinogenic sage Salvia divinorum, is an apparently selective and highly potent kappa-opioid receptor (KOR) agonist. Salvinorin A is unique among ligands for peptidergic G protein-coupled receptors in being nonnitrogenous and lipid-like in character. To examine the molecular basis for the subtype-selective binding of salvinorin A, we utilized an integrated approach using chimeric opioid receptors, site-directed mutagenesis, the substituted cysteine accessibility method, and molecular modeling and dynamics studies. We discovered that helix 2 is required for salvinorin A binding to KOR and that two residues (Val-108(2.53) and Val-118(2.63)) confer subtype selectivity. Intriguingly, molecular modeling studies predicted that these loci exhibit an indirect effect on salvinorin A binding, presumably through rotation of helix 2. Significantly, and in agreement with our in silico predictions, substituted cysteine accessibility method analysis of helix 2 comparing KOR and the delta-opioid receptor, which has negligible affinity for salvinorin A, revealed that residues known to be important for salvinorin A binding exhibit a differential pattern of water accessibility. These findings imply that differences in the helical orientation of helix 2 are critical for the selectivity of salvinorin A binding to KOR and provide a structurally novel basis for ligand selectivity.
Comparable studies
Other experimental studies on salvia divinorum, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. | 2002 | Experimental study | |
| Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells and... | 2004 | Experimental study | |
| Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. Animal model | 2014 | Experimental study | |
| Identification of the molecular mechanisms by which the diterpenoid salvinorin A binds to kappa-opioid receptors. | 2005 | Experimental study | |
| Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil. Rat brain striatum homogenates | 2009 | Laboratory experiment |
Citations in the library
Cited by 14
- Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A. Pharmacological Reviews June 1, 2011
- Structure-based design, synthesis, and biochemical and pharmacological characterization of novel salvinorin A analogues as active state probes of the kappa-opioid receptor. Biochemistry July 28, 2009
- Ligand and G-protein selectivity in the κ-opioid receptor. Nature May 1, 2023
- The hallucinogen derived from Salvia divinorum, salvinorin A, has kappa-opioid agonist discriminative stimulus effects in rats. Neuropharmacology September 1, 2007
- Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects Pharmaceuticals February 3, 2021
and 9 more in the library
Cites 11
- Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Sciences September 3, 2002
- Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations. Journal of Pharmacology and Experimental Therapeutics March 1, 2004
- Ethnopharmacology of ska María Pastora (Salvia divinorum, Epling and Játiva-M.). Journal of Ethnopharmacology May 1, 1983
- Salvinorin A: the "magic mint" hallucinogen finds a molecular target in the kappa opioid receptor. TIPS - Trends in Pharmacological Sciences March 1, 2003
- Salvia divinorum and the unique diterpene hallucinogen, Salvinorin (divinorin) A. Journal of Psychoactive Drugs 1994
and 6 more in the library