Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures

Hua, Tian; Li, Xiaoting; Wu, Lijie; Iliopoulos‐Tsoutsouvas, Christos; Wang, Yuxia; Wu, Meng; Shen, Linhan; Johnston, Christina A.; Nikas, Spyros P.; Song, Feng; Song, Xiyong; Yuan, Shuguang; Sun, Qianqian; Wu, Yiran; Jiang, Shan; Grim, Travis W.; Benchama, Othman; Stahl, Edward L.; Zvonok, Nikolai; Zhao, Suwen; Bohn, Laura M.; Makriyannis, Alexandros; Liu, Zhi Jie

doi:10.1016/j.cell.2020.01.008

Cited by 257 publications

(387 citation statements)

References 65 publications

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“…The N terminus of GnRH1R inserts into the orthosteric site but may not contribute to receptor-G q signaling activation. The N termini of GPCRs have been reported to undergo structural rearrangement when the receptor binds to an agonist 44 , 45 . Therefore, structures of GnRH1R in complex with representative agonists would aid better understanding of the properties of the N terminus of the receptor, as well as the structural features of microswitches.…”

Section: Discussionmentioning

confidence: 99%

Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

et al. 2020

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Gonadotrophin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). The GnRH-GnRH1R system is a promising therapeutic target for maintaining reproductive function; to date, a number of ligands targeting GnRH1R for disease treatment are available on the market. Here, we report the crystal structure of GnRH1R bound to the small-molecule drug elagolix at 2.8 Å resolution. The structure reveals an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix. The unusual ligand binding mode was further investigated by structural analyses, functional assays and molecular docking studies. On the other hand, because of the unique characteristic of lacking a cytoplasmic C-terminal helix, GnRH1R exhibits different microswitch structural features from other class A GPCRs. In summary, this study provides insight into the ligand binding mode of GnRH1R and offers an atomic framework for rational drug design.

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Section: Discussionmentioning

confidence: 99%

Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

et al. 2020

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“…The N-terminal α-helix of 6g79 was set as reference to align all structures. A similar alignment was done for the Gαi1 structures 1gg2 20 , 5kdo 65 , 6ddf 66 , 6osa 67 , 6n4b 68 , 6kpf 69 , and 6k42 19 , setting the N-terminal α-helix of 5kdo as reference. GalT-GFP was used as control.…”

Section: S6n Gαo-s6r Gαo-s6v Mgnc Mgntc Mgckr Mgcke Mgcdr Mgcmentioning

confidence: 99%

Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo

Solis

Valnohová

Álvarez

et al. 2020

Preprint

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Peripheral membrane proteins (PMPs) associate with cellular membranes through post-translational modifications like S-palmitoylation. The Golgi apparatus is generally viewed as the transitory station where palmitoyl acyltransferases (PATs) modify PMPs, which are then transported to their ultimate destinations such as plasma membrane (PM); little substrate specificity among the many PATs has been determined. Here we describe inherent partitioning of Gαo – α-subunit of heterotrimeric Go-proteins – to PM and Golgi, independent from Golgi-to-PM transport. A minimal code within the Gαo N-terminus governs the compartmentalization and re-coding produces G-protein versions with shifted localization. We established the SpONM (S-palmitoylation at the outer nuclear membrane) assay to probe substrate specificity of PATs in intact cells. With this assay, we showed that PATs localizing to different membrane compartments display remarkable substrate selectivity, which is the basis for specific PMP compartmentalization. Our findings uncover the fundamental mechanism governing protein localization and establish the basis for innovative drug discovery.

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“…Four are co-crystallized with a ligand: one bound to antagonist AM6538 , one bound to an inverse agonist taranabant ( TNB ) (Hua et al. ; Shao et al., 2016 ), two bound to a full agonist ( AM11542 and AM841 ) ( Hua et al., 2017 ), most recently, two Cryo-EM structure: bound to full agonist with the G i protein bound (MDMB-Fubinaca, FUB ) ( Krishna Kumar et al., 2019 ), and AM841 ( Hua et al., 2020 ). Crystallization in the presence of a phytocannabinoid remains elusive.…”

Section: Introductionmentioning

confidence: 99%

“…The first agonist-bound CB 1 crystal structure was reported in 2017 ( AM11542@CB 1 PDB: 5XRA ) ( Figure 4 B, Video S1 ) ( Hua et al., 2020 ). This structure was largely consistent with that identified by Kobilka et al.…”

Section: Introductionmentioning

confidence: 99%

Cannabinoids and Cannabinoid Receptors: The Story so Far

et al. 2020

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Like most modern molecular biology and natural product chemistry, understanding cannabinoid pharmacology centers around molecular interactions, in this case, between the cannabinoids and their putative targets, the G-protein coupled receptors (GPCRs) cannabinoid receptor 1 (CB 1 ) and cannabinoid receptor 2 (CB 2 ). Understanding the complex structure and interplay between the partners in this molecular dance is required to understand the mechanism of action of synthetic, endogenous, and phytochemical cannabinoids. This review, with 91 references, surveys our understanding of the structural biology of the cannabinoids and their target receptors including both a critical comparison of the extant crystal structures and the computationally derived homology models, as well as an in-depth discussion about the binding modes of the major cannabinoids. The aim is to assist in situating structural biochemists, synthetic chemists, and molecular biologists who are new to the field of cannabis research.

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Activation and Signaling Mechanism Revealed by Cannabinoid Receptor-Gi Complex Structures

Abstract: Highlightsand CB2-AM12033 are determined d Structural evidence of G protein selectivity by CB1 and CB2 is identified d MD simulations reveal the distinct binding behavior of HU308 in CB2 and CB1 d Cholesterol molecule as an endogenous allosteric modulator of CB1 is uncovered

Cited by 257 publications

References 65 publications

Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo

Cannabinoids and Cannabinoid Receptors: The Story so Far

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