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.