Molecular Interaction between Distal C-Terminal Domain of the CB₁ Cannabinoid Receptor and Cannabinoid Receptor Interacting Proteins (CRIP1a/CRIP1b)

We have investigated the structure of the distal C-terminal domain of the of the CB₁ cannabinoid receptor (CB1R) to study its interactions with CRIP1a and CRIP1b using computational techniques. The amino acid sequence from the distal C-terminal domain of CB1R (G⁴¹⁷-L⁴⁷²) was found to be unique, as it does not share sequence similarity with other protein structures, so the structure was predicted using ab initio modeling. The computed model of the distal C-terminal region of CB1R has a helical region between positions 441 and 455. The CRIP1a and CRIP1b were modeled using Rho-GDI 2 as a template. The three-dimensional model of the distal C-terminal domain of the CB1R was docked with both CRIP1a as well as CRIP1b to study the crucial interactions between CB1R and CRIP1a/b. The last nine residues of CB1R (S⁴⁶⁴TDTSAEAL⁴⁷²²) are known to be a CRIP1a/b binding site. The majority of the key interactions were identified in this region, but notable interactions were also observed beyond theses nine residues. The multiple interactions between Thr418 (CB1R) and Asn61 (CRIP1a) as well as Asp430 (CB1R) and Lys76 (CRIP1a) indicate their importance in the CB1R-CRIP1a interaction. In the case of CRIP1b, multiple hydrogen bond interactions between Asn437 (CB1R) and Glu77 (CRIP1b) were observed. These interactions can be critical for CB1R's interaction with CRIP1a/b, and targeting them for further experimental studies can advance information about CRIP1a/b functionality.