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

Yan, Wei; Cheng, Lin; Wang, Wei; Wu, Chao; Yang, Xin; Du, Xiaozhe; Ma, Liang; Qi, Shiqian; Wei, Yuquan; Lu, Zhi-Liang; Yang, Shengyong; Shao, Zhenhua

doi:10.1038/s41467-020-19109-w

Cited by 36 publications

(40 citation statements)

References 66 publications

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“…To facilitate crystallization, a thermostabilized apocytochrome bRIL was fused to the third intracellular loop (ICL3). Furthermore, mutations of T130 3.39 K and N188 ECL2 Q were introduced to improve the thermostability and homogeneity of the receptor as described in our previous study 32 (Supplementary Fig. 1a–d ).…”

Section: Resultsmentioning

confidence: 99%

“…IP accumulation was measured using Cisbio IP1 assay kit (Cisbio, 62IPAPEB), which has been previously described 32 . In brief, the harvested cells were distributed in a low volume 96-well dish and stimulated with increased concentration of inverse agonist PF-05190457, agonist ghrelin peptide or antagonist compound 21 containing 10 nM ghrelin peptide at 37 °C for 2 h. After that, d2-labeled IP1 and cryptate-labeled anti-IP1 monoclonal antibody dissolved in Lysis Buffer were added to the wells.…”

Section: Methodsmentioning

confidence: 99%

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Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Qin

Cai

et al. 2022

Nat Commun

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Much effort has been invested in the investigation of the structural basis of G protein-coupled receptors (GPCRs) activation. Inverse agonists, which can inhibit GPCRs with constitutive activity, are considered useful therapeutic agents, but the molecular mechanism of such ligands remains insufficiently understood. Here, we report a crystal structure of the ghrelin receptor bound to the inverse agonist PF-05190457 and a cryo-electron microscopy structure of the active ghrelin receptor-Go complex bound to the endogenous agonist ghrelin. Our structures reveal a distinct binding mode of the inverse agonist PF-05190457 in the ghrelin receptor, different from the binding mode of agonists and neutral antagonists. Combining the structural comparisons and cellular function assays, we find that a polar network and a notable hydrophobic cluster are required for receptor activation and constitutive activity. Together, our study provides insights into the detailed mechanism of ghrelin receptor binding to agonists and inverse agonists, and paves the way to design specific ligands targeting ghrelin receptors.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Qin

Cai

et al. 2022

Nat Commun

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“…SARS-CoV-2 infection has been associated with altered gonadotropin, androgen, and testosterone secretion that may disrupt male reproduction and fertility, and female menstrual cycles. The conformations of Nsp1 and GNRHR make it unlikely that they interact with each other [36,37].…”

Section: Molecular Docking Of Drugs To Nsp1 Binding Site On Nxf1-nxt1mentioning

confidence: 99%

“…(A) Our search did not identify any small nonpeptide GNRHR antagonists. These drugs have very different chemical structures honed to bind deep in the central cavity of the 7 transmembrane receptor structure (PDB 7BR3) [36,37]. Therefore, it is unlikely that activity against GNRHR, per se, will be important for determining the conformation of ganirelix for blocking Nsp1.…”

Section: Drugmentioning

confidence: 99%

Understanding COVID-19 Pathogenesis: A Drug-Repurposing Effort to Disrupt Nsp-1 Binding to Export Machinery Receptor Complex

Vasudevan

Baraniuk

2021

Pathogens

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Non-structural protein 1 (Nsp1) is a virulence factor found in all beta coronaviruses (b-CoVs). Recent studies have shown that Nsp1 of SARS-CoV-2 virus interacts with the nuclear export receptor complex, which includes nuclear RNA export factor 1 (NXF1) and nuclear transport factor 2-like export factor 1 (NXT1). The NXF1–NXT1 complex plays a crucial role in the transport of host messenger RNA (mRNA). Nsp1 interferes with the proper binding of NXF1 to mRNA export adaptors and its docking to the nuclear pore complex. We propose that drugs targeting the binding surface between Nsp1 and NXF1–NXT1 may be a useful strategy to restore host antiviral gene expression. Exploring this strategy forms the main goals of this paper. Crystal structures of Nsp1 and the heterodimer of NXF1–NXT1 have been determined. We modeled the docking of Nsp1 to the NXF1–NXT1 complex, and discovered repurposed drugs that may interfere with this binding. To our knowledge, this is the first attempt at drug-repurposing of this complex. We used structural analysis to screen 1993 FDA-approved drugs for docking to the NXF1–NXT1 complex. The top hit was ganirelix, with a docking score of −14.49. Ganirelix competitively antagonizes the gonadotropin releasing hormone receptor (GNRHR) on pituitary gonadotrophs, and induces rapid, reversible suppression of gonadotropin secretion. The conformations of Nsp1 and GNRHR make it unlikely that they interact with each other. Additional drug leads were inferred from the structural analysis of this complex, which are discussed in the paper. These drugs offer several options for therapeutically blocking Nsp1 binding to NFX1–NXT1, which may normalize nuclear export in COVID-19 infection.

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“…Phylogenetic classifications divide GnRH receptors into three [85] or five groups [129] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH 1 receptor in complex with elagolix has been elucidated [132].…”

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confidence: 99%

Gonadotrophin-releasing hormone receptors in GtoPdb v.2021.3

et al. 2021

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GnRH1 and GnRH2 receptors (provisonal nomenclature [39], also called Type I and Type II GnRH receptor, respectively [85]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [85, 84, 114]. GnRH I (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [85, 84, 114] including GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [85, 84, 114]. GnRH1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [58]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [58]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH2 receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [88]. Phylogenetic classifications divide GnRH receptors into three [85] or five groups [129] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH1 receptor in complex with elagolix has been elucidated [132].

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

Cited by 36 publications

References 66 publications

Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Molecular mechanism of agonism and inverse agonism in ghrelin receptor

Understanding COVID-19 Pathogenesis: A Drug-Repurposing Effort to Disrupt Nsp-1 Binding to Export Machinery Receptor Complex

Gonadotrophin-releasing hormone receptors in GtoPdb v.2021.3

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