Allosteric Modulation of the CB1 Cannabinoid Receptor by Cannabidiol—A Molecular Modeling Study of the N-Terminal Domain and the Allosteric-Orthosteric Coupling

Abstract

The CB1 cannabinoid receptor (CB1R) contains one of the longest N termini among class A G protein-coupled receptors. Mutagenesis studies suggest that the allosteric binding site of cannabidiol (CBD) involves residues from the N terminal domain. In order to study the allosteric binding of CBD to CB1R we modeled the whole N-terminus of this receptor using the replica exchange molecular dynamics with solute tempering (REST2) approach. Then, the obtained structures of CB1R with the N terminus were used for ligand docking. A natural cannabinoid receptor agonist, Δ9-THC, was docked to the orthosteric site and a negative allosteric modulator, CBD, to the allosteric site positioned between extracellular ends of helices TM1 and TM2. The molecular dynamics simulations were then performed for CB1R with ligands: (i) CBD together with THC, and (ii) THC-only. Analyses of the differences in the residue-residue interaction patterns between those two cases allowed us to elucidate the allosteric network responsible for the modulation of the CB1R by CBD. In addition, we identified the changes in the orthosteric binding mode of Δ9-THC, as well as the changes in its binding energy, caused by the CBD allosteric binding. We have also found that the presence of a complete N-terminal domain is essential for a stable binding of CBD in the allosteric site of CB1R as well as for the allosteric-orthosteric coupling mechanism.

Endocannabinoid signaling in the central nervous system

“…In agreement with these findings, low-micromolar concentrations of CBD inhibit DSE in hippocampal neuronal cultures in a manner consistent with a NAM mechanism of action (Straiker et al, 2018). Mutagenesis studies (Laprairie et al, 2015) and recent molecular dynamics simulations of CBD and THC docking to the CB1 receptor (Jakowiecki et al, 2021) Several CB1 receptor PAMs have also been identified. The first was the anti-inflammatory lipid, lipoxin A4 (Pamplona et al, 2012), although later studies did not find a PAM effect on DSE at cultured hippocampal neurons (Khajehali et al, 2015).…”

“…In agreement with these findings, low‐micromolar concentrations of CBD inhibit DSE in hippocampal neuronal cultures in a manner consistent with a NAM mechanism of action (Straiker et al, 2018). Mutagenesis studies (Laprairie et al, 2015) and recent molecular dynamics simulations of CBD and THC docking to the CB1 receptor (Jakowiecki et al, 2021) both indicate that the allosteric binding site of CBD involves residues from the N terminal domain and the second extracellular loop. This is a different region of the receptor than occupied by ORG27569 discussed above, suggesting that there are multiple mechanisms of CB1 receptor allosterism.…”

Distinct Binding Mechanisms for Allosteric Sodium Ion in Cannabinoid Receptors

“…42,43 Prof. Slawomir Filipek's group at the University of Warsaw, Poland, also generously provided a previous CB 1 structure for comparison. 44 In ∼10 μs simulations, we observed that N-terminus does not have an effect on Na + binding (refer to the Supporting Information for detailed discussion). Therefore, the simulations were performed with the truncated N-termini from the crystal structures, where truncated N-termini were capped by adding the acetyl (ACE) capping group.…”

“…Thermostabilized residues in the protein crystal structure were mutated back according to the original protein sequence. , In these structures, the N-termini of CB 1 and CB 2 are truncated by 98 and 20 residues, respectively. To observe the effect of the N-terminus on Na + from the extracellular region, we modeled the N-terminus of both proteins using Rosetta. , Prof. Slawomir Filipek’s group at the University of Warsaw, Poland, also generously provided a previous CB 1 structure for comparison . In ∼10 μs simulations, we observed that N-terminus does not have an effect on Na + binding (refer to the Supporting Information for detailed discussion).…”

Impact of Cannabinoid Compounds on Skin Cancer

“…In another in vitro study, CBD was found to act as a non-competitive antagonist of both CB 1 and CB 2 receptor agonists [ 41 ]. In a recently published molecular dynamics simulation, it was also shown that CBD binding to the N-terminal domain of the CB 1 receptor leads, in the sense of a negative allosteric regulation, to a change in the orthosteric binding mode of THC [ 42 ]. This could provide a plausible explanation for CBD counteracting some of the negative side effects of THC, such as intoxication, sedation, and tachycardia (for a review, see [ 43 ]).…”