Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex

Abstract

Graphical AbstractHighlights d 3 Å cryo-EM structure of the CB1-G i complex bound to potent agonist MDMB-Fubinaca d MDMB-Fubinaca locks ''toggle switch'' residues F200 3.36 / W356 6.48 in active conformation d Quantum mechanics calculations reveal the mechanism for the high affinity of Fubinaca d Molecular dynamic simulations reveal a path for ligand entry between TM1 and TM7 In BriefLooking at how a toxic, synthetic ligand locks cannabinoid receptor 1 into a signaling conformation points to ways to understand and modulate receptor activity. SUMMARYCannabis elicits its mood-enhancing and analgesic effects through the cannabinoid receptor 1 (CB1), a G protein-coupled receptor (GPCR) that signals primarily through the adenylyl cyclase-inhibiting heterotrimeric G protein G i . Activation of CB1-G i signaling pathways holds potential for treating a number of neurological disorders and is thus crucial to understand the mechanism of G i activation by CB1. Here, we present the structure of the CB1-G i signaling complex bound to the highly potent agonist MDMB-Fubinaca (FUB), a recently emerged illicit synthetic cannabinoid infused in street drugs that have been associated with numerous overdoses and fatalities. The structure illustrates how FUB stabilizes the receptor in an active state to facilitate nucleotide exchange in G i . The results compose the structural framework to explain CB1 activation by different classes of ligands and provide insights into the G protein coupling and selectivity mechanisms adopted by the receptor.

Functional evaluation of carboxy metabolites of synthetic cannabinoid receptor agonists featuring scaffolds based on L‐valine or L‐tert‐leucine

“…Consequently, compound 21 has been designated as one of the deadliest cannabimimetics sold to date . Interestingly, the structure of this highly potent agonist bound to the CB 1 ‐Gα i complex has recently been unraveled . Delineating the structural basis of this complex revealed a C‐shape binding mode of 21 , which stabilizes the active conformation of CB 1 to a greater extent compared to the partial agonist Δ 9 ‐THC.…”

“…Its structural analog, MDMB‐FUBINACA ( 21 ), has similarly been linked to more than 600 poisonings, including 15 deaths over 2 weeks in Russia in 2014 . Consequently, compound 21 has been designated as one of the deadliest cannabimimetics sold to date . Interestingly, the structure of this highly potent agonist bound to the CB 1 ‐Gα i complex has recently been unraveled .…”

Detection and quantitation of synthetic cannabinoid receptor agonists in infused papers from prisons in a constantly evolving illicit market

“…Synthetic cannabinoid receptor agonists are a structurally diverse class of compounds that interact with human cannabinoid type 1 and type 2 G-protein coupled receptors (GPCRs), CB 1 and CB 2. [15][16][17][18][19] They vary widely in their potency and efficacy [20][21][22] as a result of differences in their structural conformation, including chirality. 23 Their diversity is due, in part, to the increased online availability of published research studies and patents describing their synthesis, in vitro potency and efficacy, and biological effects; the availability of precursor materials;…”

Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

“…While 11 acts as a partial agonist at the CB 1 receptor, SCRAs typically demonstrate full agonist activity at both the CB 1 and CB 2 receptor . The CB 1 receptor has been suggested to undergo conformational changes upon agonist binding and activation, through hydrophobic interactions with the “toggle twin switch” (comprising phenylalanine residue F200 3.25 and tryptophan residue W365 6.48 of CB 1 ) . Differences in the mode of ligand interaction with the “toggle twin switch” between the indazole SCRA, MDMB‐FUBINACA ( 12 ), and Δ 9 ‐THC ( 11 ) have been posited as a potential reason for the observed efficacy of 12 (relative to 11 ).…”