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-Structure paper
タイトル | Structural basis of Δ-THC analog activity at the Cannabinoid 1 receptor. |
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ジャーナル・号・ページ | Res Sq, Year 2024 |
掲載日 | 2024年5月21日 |
著者 | David Gloriam / Thor Thorsen / Yashraj Kulkarni / David Sykes / Andreas Bøggild / Taner Drace / Pattarin Hompluem / Christos Iliopoulos-Tsoutsouvas / Spyros Nikas / Henrik Daver / Alexandros Makriyannis / Poul Nissen / Michael Gajhede / Dmitry Veprintsev / Thomas Boesen / Jette Kastrup |
PubMed 要旨 | Δ-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. ...Δ-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. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB and its primary transducer, G. 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 and β-arrestins and reversibility of binding from an active complex. By combining detailed CB 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. |
リンク | Res Sq / PubMed:38826401 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.9 Å |
構造データ | EMDB-19929, PDB-9erx: |
化合物 | PDB-1h66: ChemComp-HOH: |
由来 |
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キーワード | MEMBRANE PROTEIN / GPCR / Cannabinoid receptor 1 / THC analog complex |