Building 3D-structural model of kappa opioid receptor and studying its interaction mechanism with dynorphin A(1-8)

To construct the 3D-structural model of human kappa opioid receptor (HKOR) and study its interacting mechanism with dynorphin A(1-8) (Dyn8).

Comparative molecular modeling was applied to build the 7 transmembrane (TM) helical domain of HKOR using the bovine rhodopsin (OPSD) model as a template. Molecular dynamics was performed to minimize the HKOR model and to simulate the 3D-structure of Dyn8 based on the NMR results of dynorphin A(1-14). The extracellular loops (EL) were built by self-constructed database searching. DOCK4.0 program was performed to construct Dyn8 complex with HKOR.

(1) The model of HKOR was obtained and validated by theoretical and experimental data. (2) The Dyn8-HKOR interacting mechanism is reasonably explained: Side chain of residue Asp138 interacts with protonated nitrogen atom at the N-terminal residues of Dyn8 through electrostatic and hydrogen bonding, which play an important role in ligand binding with receptor. (3) Negatively charged amino acids in the second extracellular loop (EL2) as Asp223 and Glu209 interact with the C-terminal positively charged residues in Dyn8, and Glu209 is a likely determinant of peptide ligand specificity.

Some amino acid residues positioned in EL2, TM3, TM4, and TM5 form the binding site and therefore determine the selectivity of kappa peptide agonist.