1. Allosteric Modulation of the CB1 Cannabinoid Receptor by Cannabidiol—A Molecular Modeling Study of the N-Terminal Domain and the Allosteric-Orthosteric Coupling.
- Author
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Jakowiecki, Jakub, Abel, Renata, Orzeł, Urszula, Pasznik, Paweł, Preissner, Robert, Filipek, Sławomir, and Bisi, Alessandra
- Subjects
MOLECULAR dynamics ,G protein coupled receptors ,N-terminal residues ,CANNABIDIOL ,ALLOSTERIC regulation ,MUSCARINIC acetylcholine receptors ,CANNABINOID receptors ,BINDING energy - Abstract
The CB
1 cannabinoid receptor (CB1 R) 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 CB1 R 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 CB1 R 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 CB1 R 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 CB1 R 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 CB1 R as well as for the allosteric-orthosteric coupling mechanism. [ABSTRACT FROM AUTHOR]- Published
- 2021
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