Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1

Yang, Xin; Wang, Xuehui; Xu, Zheng; Wu, Chao; Zhou, Yangli; Wang, Yifei; Lin, Guifeng; Li, Kan; Wu, Ming; Xia, Anjie; Liu, Jingming; Cheng, Lin; Zou, Jun; Yan, Wei; Shao, Zhenhua; Yang, Shengyong

doi:10.1038/s41589-022-01038-y

Cited by 54 publications

(69 citation statements)

References 60 publications

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“…Since, otherwise the maps are very similar, we use only the ZCZ-bound map (as our previous FUB-bound structure was also obtained in the presence of ZCZ) for further discussions. Recently, structures of CB1 bound to ZCZ were determined, showing binding site involving TMs 2, 3 and 4 11 . In neither of our structures do we see any density in the region described in the previous study 11 and hence, we do not model either of the PAMs (ZCZ and AM11517) in our structures.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, structures of CB1 bound to ZCZ were determined, showing binding site involving TMs 2, 3 and 4 11 . In neither of our structures do we see any density in the region described in the previous study 11 and hence, we do not model either of the PAMs (ZCZ and AM11517) in our structures. Overall, the mode of G i engagement with the endo-bound CB1 is very similar to the previously determined structure of FUB-bound CB1 complex, except for ∼ 4 Å deviation of the αN of G i between the CB1-G i complexes (Fig S2a).…”

Section: Resultsmentioning

confidence: 99%

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Modulation of cannabinoid receptor signaling by endocannabinoids

Kumar¹,

Robertson²,

Thadhani³

et al. 2022

Preprint

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Endocannabinoids (eCBs) are endogenous lipid molecules that activate the cannabinoid receptor 1 (CB1), a G protein coupled receptor (GPCR) that signals primarily through the Gi/o family of G proteins to regulate neurotransmitter release. Consequently, CB1 is an important therapeutic target for several neurological disorders. How eCBs interact with CB1 is not known and the downstream signaling they activate is not well understood. In this study we show that eCBs do not activate Gi1 as much as synthetic cannabinoids. To characterize activation of CB1 by eCB, we formed an eCB analogue-bound (AMG315) CB1-Gi signaling complex for structural studies. The structure reveals differences in the orthosteric ligand binding pocket not seen in the previous CB1 structures, providing insights into the structural determinants of ligand efficacy. In combination with signaling and simulation data, this study provides mechanistic insights into CB1 activation by different classes of ligands, and sheds light on the G protein preferences between endogenous and exogenous ligands.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Modulation of cannabinoid receptor signaling by endocannabinoids

Kumar¹,

Robertson²,

Thadhani³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…It should be noted that, although our simulations indicated that stacking or T-shape aromatic interactions between F155 2.42 and F237 4.46 may form transiently in a dynamic context (Figure S9), aromatic interactions between these residues are not present in CB1 crystal structures. Moreover, in mutagenesis experiments the replacement of F155 2.42 by V, an aliphatic but smaller side chain, was shown to increase G i signaling; in contrast, mutation to the aromatic but larger W had the opposite effect . These results suggest the aromaticity of F155 2.42 might not be the determinant factor for its role in the activation process, and also the possibility that the size of the side chain at this location might be important.…”

Section: Discussionmentioning

confidence: 96%

Evaluating Allosteric Perturbations in Cannabinoid Receptor 1 by In Silico Single-Point Mutation

2022

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Cannabinoid receptor 1 (CB1) is a promising drug target involved in many physiological processes. Using atomistic molecular dynamics (MD) simulations, we examined the structural effect of F237L mutation on CB1, a mutation that has qualitatively similar effects to allosteric ligand ORG27569 binding. This mutation showed a global effect on CB1 conformations. Among the observed effects, TM6 outward movement and the conformational change of the NPxxY motif upon receptor activation by CB1 agonist CP55940 were hindered compared to wt CB1. Within the orthosteric binding site, CP55940 interactions with CB1 were altered. Our results revealed that allosteric perturbations introduced by the mutation had a global impact on receptor conformations, suggesting that the mutation site is a key region for allosteric modulation in CB1.

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“…By comparing the 6d-bound receptor structure with the inactive crystal structure, it can be found that the orthosteric site bound with the agonist exhibits shrinkage. Throughout the simulation, the receptor was in an active-like state as the intracellular region of TM6 was clearly moving outward (this is the most prominent activation feature of class A GPCRs), 25 resulting in the separation of residues (R139 3.50 and T265 6.33 ) whose distances increased from 7.9 Å to greater than 11.0 Å (Figure 9B). The stable hydrogen bond interaction between W280 6.48 and N315 7.45 makes TM7 cooperate with TM6 to undergo a conformational change (Figure 13A).…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…The initial inactive GnRH1R structure was obtained from the GnRH1R-elagolix inactive crystal structure (PDB code: 7BR3). The initial active-like conformation of GnRH1R was downloaded from the GPCRdb website, , a homology model built with the help of MODELLER . For all simulations, we removed the cocrystallized fusion protein from the structure.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

Yang

Lin

Xia

et al. 2022

J. Chem. Inf. Model.

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The gonadotrophin-releasing hormone (GnRH) is a central regulator of the human reproductive system and exerts physiological effects by binding to GnRH1R. The GnRH–GnRH1R system is a promising therapeutic target for the maintenance of reproductive function. There are several GnRH1R agonists on the market, but like GnRH, they are all peptide compounds and are limited by their way of administration (subcutaneous or intramuscular injection). To date, no published GnRH1R small molecule agonists have been reported. In this paper, the HTRF-based screening method has been used to screen our in-house chemical library, and we found and confirmed CD304 as a hit compound. Subsequently, structure optimization led to the discovery of compound 6d, exhibited with a certain GnRH1R activation activity (EC50: 1.59 ± 0.38 μM). Further molecular dynamics simulation experiments showed that 6d can well bind to the orthosteric site of GnRH1R through forming a hydrogen-bonding interaction with Y2836.51. Binding of 6d further induces conformational changes in TM6 and TM7, promoting the formation of a continuous water channel in GnRH1R, thereby promoting GnRH1R activation. This well-characterized hit compound will facilitate the further development of novel small molecule agonists of GnRH1R.

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Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1

Cited by 54 publications

References 60 publications

Modulation of cannabinoid receptor signaling by endocannabinoids

Modulation of cannabinoid receptor signaling by endocannabinoids

Evaluating Allosteric Perturbations in Cannabinoid Receptor 1 by In Silico Single-Point Mutation

Discovery of Small Molecule Agonist of Gonadotropin-Releasing Hormone Receptor (GnRH1R)

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