Structure of an allosteric modulator bound to the CB1 cannabinoid receptor

Shao, Zhenhua; Yan, Wei; Chapman, Karen; Ramesh, Karthik; Ferrell, Aaron J.; Yin, Jie; Wang, Xuehui; Xu, Qingping; Rosenbaum, Daniel M.

doi:10.1038/s41589-019-0387-2

Cited by 135 publications

(179 citation statements)

References 52 publications

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“…As shown in Fig 4, the equilibrated poses share the binding region in the orthosteric binding pocket well with the cannabinoid ligands in the orthosteric binding pocket as found in the X-ray crystal structures of the AM11542-bound CB1 receptor [6] and the CP55940-bound CB1 receptor [7]. Each of the eight equilibrated poses adopts an extended conformation that spans throughout the binding core region.…”

Section: Resultsmentioning

confidence: 73%

“…All the eight equilibrated poses (in atom type) are overlaid to AM11542 (in green) and CP55940 (in mauve) after the receptor in these poses were superimposed to the receptors in the X-ray crystal structures of the AM11542-bound CB1 receptor [6] and the CP55940-bound CB1 receptor [7]. The alignment rule: the backbone Cα atoms of H3 (Arg186-Ser217), H4 (Arg230-Val249), H5 (Glu273-Val306) and H7 (Lys373-Arg400).…”

Section: Resultsmentioning

confidence: 99%

“…(C) AEA docking pose Group 3 ( docking pose7 and docking pose8 ). The eight docking poses (in white) and equilibrated poses (in atom type) were superimposed to AM11542 (in green) and CP55940 (in mauve) in the X-ray crystal structures of AM11542-bound CB1 receptor [6] and CP55940-bound CB1 receptor [7]. The alignment rule of the receptors is same as in Fig 4.…”

Section: Resultsmentioning

confidence: 99%

“…After overlaid to the cannabinoid ligands in the orthosteric binding pocket as found in the X-ray crystal structures of the AM11542-bound CB1 receptor [6] and the CP55940-bound CB1 receptor [7], the eight equilibrated poses became merged into 1_H7, 1_H2/H3 and 2d_H2/H3 (Fig 6). No AEA equilibrated pose is found such that the tail moiety of AEA binds the deep hydrophobic channel (Figs 6A and 6B).…”

Section: Resultsmentioning

confidence: 99%

“…Recently determined X-ray crystal structures of the CB1 receptor in complex with various ligands [4-7] have revealed the detailed receptor interactions with the bound ligand. Toward understanding molecular mechanisms of marijuana action, these X-ray crystal structures have also shed light on how the ligand activates the receptor upon binding at the molecular level.…”

Section: Introductionmentioning

confidence: 99%

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Prediction of Essential Binding Domains for the Endocannabinoid N-Arachidonoylethanolamine (AEA) in the Brain Cannabinoid CB1 receptor

Shim

2020

Preprint

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20∆ 9 -tetrahydrocannabinol (∆ 9 -THC), the main active ingredient of Cannabis sativa 21 (marijuana), interacts with the human brain cannabinoid (CB1) receptor and mimics 22 pharmacological effects of endocannabinoids (eCBs) N-arachidonylethanolamide (AEA) and 2-23 arachidonoylglycerol (2-AG). Given recent intriguing findings that some allosteric modulators 24 can enhance selectively the AEA-activated CB1 receptor, it is imperative to determine the 25 structure of the AEA-bound CB1 receptor. However, due to its highly flexible nature of AEA, 26 establishing its binding mode to the CB1 receptor is elusive. The aim of the present study was to 27 explore many possible binding conformations of AEA within the binding pocket of the CB1 28 receptor that is confirmed in the recently available X-ray crystal structures of the agonist-bound 29 CB1 receptors and predict essential AEA binding domains. We performed long time molecular 30 dynamics stimulations of plausible AEA docking poses until its receptor binding interactions 31 became optimally established. Our simulation results revealed that AEA favors to bind to the 32 hydrophobic channel of the CB1 receptor, suggesting that the hydrophobic channel holds 33 essential significance in AEA binding to the CB1 receptor. Our results also suggest that the 34 H2/H3 region of the CB1 receptor is an AEA binding subsite privileged possibly over the H7 35 region. The results of the present study contribute to identifying the (hidden) allosteric site(s) of 36 the CB1 receptor in our immediate future study.37 38 39 40 41 3 42 4 65 adopt millions of conformations. Identification of the bioactive conformation of AEA to the CB1 66receptor can be quite elusive due to its potential to adopt many low-energy binding 67 conformations only a few of which would be responsible for receptor activation. AEA is a partial 68 agonist at CB1 receptors [16,17] just like Δ 9 -THC but somewhat more potent than Δ 9 -THC in 69 activating the CB1 receptor [1]. Without any known X-ray crystal structure of the AEA-bound 70 CB1 receptor, the nature of binding interactions of AEA with the CB1 receptor remains poorly 71 understood. 72 73 106 AM11542 bound to the CB1 receptor in the X-ray crystal structure of the AM11542-bound CB1 107 receptor [6]. A typical setting of docking parameters for performing AutoDock runs using a 108 hybrid global-local Lamarkian genetic algorithm (LGA) [24] were: the rate of gene mutation 109 (0.02), rate of crossover (0.8), GA window size (10), the number of individuals in population 110 (150), the maximum number of energy evaluations in each run (25,000,000), the maximum 6 111 number of generations (27,000) and the number of LGA docking runs (10). Only the ligand was 112 allowed to freely move inside the grid box while the protein was rigidly fixed in position. The 113 resulting docking poses were evaluated by the AutoDock4 scoring function [25]. AutoDock runs 114were performed more than one hundred times using the best scoring docking pose from the 115 previous run as the star...

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Section: Resultsmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Prediction of Essential Binding Domains for the Endocannabinoid N-Arachidonoylethanolamine (AEA) in the Brain Cannabinoid CB1 receptor

Shim

2020

Preprint

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Fenofibrate Recognition and G_q Protein Coupling Mechanisms of the Human Cannabinoid Receptor CB1

Wang,

Tang,

Zhao

et al. 2024

Advanced Science

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The G‐protein‐coupled human cannabinoid receptor 1 (CB1) is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. The structures of CB1‐Gi complexes in synthetic agonist‐bound forms have been resolved to date. However, the commercial drug recognition and Gq coupling mechanisms of CB1 remain elusive. Herein, the cryo‐electron microscopy (cryo‐EM) structure of CB1‐Gq complex, in fenofibrate‐bound form, at near‐atomic resolution, is reported. The structure elucidates the delicate mechanisms of the precise fenofibrate recognition and Gq protein coupling by CB1 and will facilitate future drug discovery and design.

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Endocannabinoid signaling in the central nervous system

Ramirez

Ruiz‐Pérez

Stollenwerk

et al. 2022

Glia

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It is hard to overestimate the influence of the endocannabinoid signaling (ECS) system on central nervous system (CNS) function. In the 40 years since cannabinoids were found to trigger specific cell signaling cascades, studies of the ECS system continue to cause amazement, surprise, and confusion! CB1 cannabinoid receptors are expressed widely in the CNS and regulate cell-cell communication via effects on the release of both neurotransmitters and gliotransmitters. CB2 cannabinoid receptors are difficult to detect in the CNS but seem to "punch above their weight" as compounds targeting these receptors have significant effects on inflammatory state and behavior. Positive and negative allosteric modulators for both receptors have been identified and examined in preclinical studies. Concentrations of the endocannabinoid ligands, N-arachidonoylethanolamine and 2-arachidonoylglycerol (2-AG), are regulated by a combination of enzymatic synthesis and degradation and inhibitors of these processes are available and making their way into clinical trials. Importantly, ECS regulates many essential brain functions, including regulation of reward, anxiety, inflammation, motor control, and cellular development. While the field is on the cusp of preclinical discoveries providing impactful clinical and therapeutic insights into many CNS disorders, there is still much to be learned about this remarkable and versatile modulatory system.

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Structure of an allosteric modulator bound to the CB1 cannabinoid receptor

Cited by 135 publications

References 52 publications

Prediction of Essential Binding Domains for the Endocannabinoid N-Arachidonoylethanolamine (AEA) in the Brain Cannabinoid CB1 receptor

Prediction of Essential Binding Domains for the Endocannabinoid N-Arachidonoylethanolamine (AEA) in the Brain Cannabinoid CB1 receptor

Fenofibrate Recognition and G_q Protein Coupling Mechanisms of the Human Cannabinoid Receptor CB1

Endocannabinoid signaling in the central nervous system

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Structure of an allosteric modulator bound to the CB1 cannabinoid receptor

Cited by 135 publications

References 52 publications

Prediction of Essential Binding Domains for the Endocannabinoid N-Arachidonoylethanolamine (AEA) in the Brain Cannabinoid CB1 receptor

Prediction of Essential Binding Domains for the Endocannabinoid N-Arachidonoylethanolamine (AEA) in the Brain Cannabinoid CB1 receptor

Fenofibrate Recognition and Gq Protein Coupling Mechanisms of the Human Cannabinoid Receptor CB1

Endocannabinoid signaling in the central nervous system

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Product

Resources

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Fenofibrate Recognition and G_q Protein Coupling Mechanisms of the Human Cannabinoid Receptor CB1