A unique binding epitope for salvinorin A, a non‐nitrogenous kappa opioid receptor agonist
Brian E. Kane, Marcelo J. Nieto, Christopher R. McCurdy, David M. Ferguson
The FEBS Journal May 1, 2006 DOI: 10.1111/j.1742-4658.2006.05212.x
Summary
AI-generated from the abstractSalvinorin A, a potent kappa opioid receptor agonist, binds to a specific cluster of residues in transmembrane helices II and VII, including Q115, Y119, Y312, Y313, and Y320, rather than to traditional opioid binding sites. A model is proposed where the ligand aligns vertically between these helices, spanning residues one to two turns down the helix faces. The extracellular loop 2 (EL-2) plays an indirect role in binding and selectivity. These findings clarify the structural basis for salvinorin A's unique binding and selectivity.
Study at a glance
| Characteristics | Experimental study using chimeric and single-point mutant opioid receptors Peer reviewed |
|---|---|
| Population | Chimeric and mutant opioid receptors |
| Key finding | Salvinorin A binds to a cluster of residues in TM II and VII, and a vertical alignment model between these helices is proposed. |
Abstract
Salvinorin A is a potent kappa opioid receptor (KOP) agonist with unique structural and pharmacological properties. This non‐nitrogenous ligand lacks nearly all the structural features commonly associated with opioid ligand binding and selectivity. This study explores the structural basis to salvinorin A binding and selectivity using a combination of chimeric and single‐point mutant opioid receptors. The experiments were designed based on previous models of salvinorin A that locate the ligand within a pocket formed by transmembrane (TM) II, VI, and VII. More traditional sites of opioid recognition were also explored, including the highly conserved aspartate in TM III (D138) and the KOP selectivity site E297, to determine the role, if any, that these residues play in binding and selectivity. The results indicate that salvinorin A recognizes a cluster of residues in TM II and VII, including Q115, Y119, Y312, Y313, and Y320. Based on the position of these residues within the receptor, and prior study on salvinorin A, a model is proposed that aligns the ligand vertically, between TM II and VII. In this orientation, the ligand spans residues that are spaced one to two turns down the face of the helices within the receptor cavity. The ligand is also in close proximity to EL‐2 which, based on chimeric data, is proposed to play an indirect role in salvinorin A binding and selectivity.