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

Maya Petgrave, Shubham Devesh Ramgoolam, Aravindhan Ganesan

Journal of chemical information and modeling 2024 Jan 22

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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.

Citation

Maya Petgrave, Shubham Devesh Ramgoolam, Aravindhan Ganesan. Deciphering the Molecular Association of Human CRIP1a with an Agonist-Bound Cannabinoid Receptor 1. Journal of chemical information and modeling. 2024 Jan 22;64(2):499-517