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Structural basis of D9-THC analog activity at the Cannabinoid 1 receptor
Structural highlights
FunctionGNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[1] [2] Publication Abstract from PubMedDelta(9)-tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB(1). Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB(1) and its primary transducer, G(i1). We leverage this structure for docking and 1,000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of G(i) and beta-arrestins and reversibility of binding from an active complex. By combining detailed CB(1) structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines. Structural basis of Delta(9)-THC analog activity at the Cannabinoid 1 receptor.,Gloriam D, Thorsen T, Kulkarni Y, Sykes D, Boggild A, Drace T, Hompluem P, Iliopoulos-Tsoutsouvas C, Nikas S, Daver H, Makriyannis A, Nissen P, Gajhede M, Veprintsev D, Boesen T, Kastrup J Res Sq [Preprint]. 2024 May 21:rs.3.rs-4277209. doi: 10.21203/rs.3.rs-4277209/v1. PMID:38826401[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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