Structural basis of Δ9-THC analog activity at the Cannabinoid 1 receptor.

TY - UNPB

T1 - Structural basis of Δ9-THC analog activity at the Cannabinoid 1 receptor.

AU - Gloriam, David

AU - Thorsen, Thor

AU - Kulkarni, Yashraj

AU - Sykes, David

AU - Bøggild, Andreas

AU - Drace, Taner

AU - Hompluem, Pattarin

AU - Iliopoulos-Tsoutsouvas, Christos

AU - Nikas, Spyros

AU - Daver, Henrik

AU - Makriyannis, Alexandros

AU - Nissen, Poul

AU - Gajhede, Michael

AU - Veprintsev, Dmitry

AU - Boesen, Thomas

AU - Kastrup, Jette

PY - 2024/5/21

Y1 - 2024/5/21

N2 - Δ 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 β-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.

AB - Δ 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 β-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.

U2 - 10.21203/rs.3.rs-4277209/v1

DO - 10.21203/rs.3.rs-4277209/v1

M3 - Preprint

C2 - 38826401

T3 - Research square

BT - Structural basis of Δ9-THC analog activity at the Cannabinoid 1 receptor.

ER -