Deciphering the Molecular Association of Human CRIP1a with an Agonist-Bound Cannabinoid Receptor 1

Cannabinoid receptor 1 (CB1) is a class A G-protein-coupled receptor that plays important roles in several physiological and pathophysiological processes. Therefore, targeted regulation of CB1 activity is a potential therapeutic strategy for several diseases, including neurological disorders. Apart from cannabinoid ligands, CB1 signaling can also be regulated by different CB1-associated proteins. In particular, the cannabinoid receptor interacting protein 1a (CRIP1a) associates with an activated CB1 receptor and alters the G-protein selectivity, thereby reducing the agonist-mediated signal transduction of the CB1 receptor. Experimental evidence suggests that two peptides corresponding to the distal and central C-terminal segments of CB1 could interact with CRIP1a. However, our knowledge of the molecular basis of CB1-CRIP1a recognition is still limited. In this work, we use an extensive combination of computational methods to build the first comprehensive atomistic model human CB1-CRIP1a complex. Our model provides novel structural insights into the interactions of CRIP1a with a membrane-embedded, complete, agonist-bound CB1 receptor in humans. Our results highlight the key residues that stabilize the CB1-CRIP1a complex, which will be useful to guide in vitro mutagenesis experiments. Furthermore, our human CB1-CRIP1a complex presents a model system for structure-based drug design to target this physiologically important complex for modulating CB1 activity.