Abstract (deu)
Cannabinoid receptor 1 (CB1R) and oxytocin receptor (OTR) are class A G-protein coupled receptors that play an important role in a wide range of physiological and pathological pro-cesses. Since they are essential for numerous overlapping functions in the brain, they are considered attractive drug targets.
The structures of the receptors are available individually, each of the receptors is known to form both homodimers and heterodimers, however little is known about interaction, interface, and stability of the OTR-CB1 complex. Therefore, this work aims to gain knowledge about the CB1R-OTR complex by creating and examining a model of the receptor dimer using different computational tools.
First, the heterodimeric protein complex was generated by protein-protein docking. Afterwards, twelve heterobivalent ligands were created and docked to the protein complex and these protein complexes with their related heterobivalent ligands were then solvated and inserted in a membrane bilayer. Molecular dynamics simulations were performed for each complex and the results were analyzed regarding their stability and behaviour in the membrane. Analysis of key residues involved in the complex formation was performed through site-specific mutations. We were able to show high stability for nine out of the twelve receptor complexes with their related heterobivalent ligands. The core domain is located between TMH4 of the CB1R and TMH7 of the OTR and further interactions at the interfaces were shown between TMH2 and TMH1 of the CB1R and TMH1 of the OTR, TMH3 of the CB1R, and TMH7 of the OTR as well as TMH4 of the CB1R and TMH6/7 of the OTR. Outside the interface at the TMHs, interactions of residues at ECL1, ECL2, ICL1, ICL2, ICL3, and H8 of the CB1R and residues at the N-terminus, ICL3, ECL3, H8, and C-terminus of the OTR were identified. The number of involved amino acids varied among the twelve investigated interfaces. Moreover, hydrogen bonds were found to be located mainly at the extracellular and intracellular sides of the receptor complexes, and only a few hydrogen bonds are located at the transmembrane region of the receptor complexes.