Molecular simulation of dynorphin A-(1-10) binding to extracellular loop 2 of the κ-opioid receptor. A model for receptor activation

The structure of the second extracellular loop region (EL2) of the κ-opioid receptor has been explored in an effort to understand the structural basis for dynorphin A binding and selectivity. Application of secondary structure prediction methods and homology modeling resulted in a turn-helix motif for the N-terminal region of κ-EL2. A similar motif was not predicted for EL2 of either the δ or μ opioid receptors. The EL2 helix was further shown to be amphiphilic and complementary to the helical component of dynorphin A. Using a model of the κ-receptor (Metzger et al. Neurochem. Res. 1996, 21, 1287−1294), including the newly predicted EL2 turn-helix domain, a binding mode is proposed based on helix−helix interactions between hydrophobic residues of EL2 and the helical component of dynorphin A-(1−10). Molecular simulations of the receptor−ligand complex yielded structures in which the tyramine moiety or opioid “message” of dynorphin is bound within a conserved aromatic pocket in the transmembrane domain whil...