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 while the helical portion contacted residues in EL2 and in the extracellular end of transmembrane helices 6 and 7. The model is in general agreement with site- directed mutagenesis data and chimera studies that have identified binding domains in both the EL2 and transmembrane regions to dynorphin A. The results confirm the importance of the opioid 'message' displayed by many opioid ligands but also suggest a potential mechanism of receptor activation that may be mediated by EL2 through interactions with the 'address' component of dynorphin A.