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Sandbox Reserved 1646

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This Sandbox is Reserved from 26/11/2020, through 26/11/2021 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1643 through Sandbox Reserved 1664.

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Gonadotropin releasing hormone 1 receptor (GnRHR)

It is a member of the seven-transmembrane, rhodopsin like G-protein coupled receptor (GPCR) family^[1] and is activated by the peptide hormone gonadotropin-releasing hormone (GnRH) or the rhodopsin like synthetic agonist). The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate ^[2]. Its activity is critical for successful reproductive function. Several diseases are associated with a dysfunction of this receptor or the corresponding signaling cascade.

1 Biological Function
2 Disease
3 Relevance
4 Structure
- 4.1 General structure

Biological Function

The gonadotropin releasing hormone 1 receptor is located in the plasmic membrane of pituitary gonadotrope cells in the anterior pituitary, a major organ of the endocrine system in the brain. It is activated by the gonadotropin releasing hormone (GnRH) which acts upon GnRHRs as the key regulator of puberty and reproduction. This peptide hormone is produced in the hypothalamus but gets secreted and acts upon GnRHRs in the anterior pituitary to exert its effects on reproductive maturation. The activation of the receptor, associates with G-proteins, leads to the releasing of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH) by activating several signaling cascades. These pathways mainly corresponds to the inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), MAPK, and adenyl cyclase pathways. ^[3].

Disease

A mutation or a dysfonctionnement of the receptor could cause diseases impacting the reproduction function. More generally, the dysfonctionnement of the pathways involving GnRH and its receptor leads to endocrine pathologies called hypogonadism. ^[4] It exits many types of hypogonadism but the one involving the mutation of the receptor is the idiopatic hypogonadotropic hypogonadism (IHH). In this case, the mutation leads to failure of detectable ligand binding causing the decreased efficiency of the inisitol pathway and consequently leading to the decrease of the LH, FSH, and sex steroid secretions ^[5].

Moreover, the activity the pathways related to the receptor and its localisation can cause cancer. ^[6]

Relevance

The main uses of the couple GnRH - GnRHR in the medicine field are to cure hormone-dependent diseases and assisted reproductive techniques. For instance, an agonist of GnRH is used for fertility preservation as an alternative of cryopreservation ^[7]. In addition it is a promising therapeutic target for the treatment of conditions including uterine ﬁbroids ^[8], endometriosis ^[9], and prostate cancer ^[10].

Besides, concerning animals, the GnRH receptor could be a good target for contraception with a DNA vaccine ^[11]

Structure

General structure

GnRH1R has the overall architecture of seven canonical transmembrane (TM) helices with connecting extra- and intracellular loop domains (ECL/ICL) similar to rhodopsin like receptors. However, it lacks the typically occurring cytoplasmic C-terminal helix and has an unusual ligand binding mode. The structural variation between existing GnRHR Typ I, II and III in different species has been analyzed ^[12]. First crystallographic structure analysis of human GnGH1R serve the investigation of the molecular mechanism of the receptor ^[13]

Retrieved from "http://52.214.119.220/wiki/index.php/Sandbox_Reserved_1646"

@@ Line 24: / Line 24: @@
 === General structure ===
-GnRH1R has the overall architecture of seven canonical transmembrane (TM) helices with connecting extra- and intracellular loop domains (ECL/ICL) similar to [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin like receptors]. However, it lacks the typically occurring cytoplasmic C-terminal helix and has an unusual ligand binding mode. The structural variation between existing GnRHR Typ I, II and III in different species has been analyzed <ref>DOI: 10.1210/er.2003-0002</ref>. First crystallographic structure analysis of human GnGH1R serve the investigation of the molecular mechanism of the receptor (2). In this analysis the GnRH1R contains certain modifications: ICL3 (aa 243-256) is replaced by the Pyrococcus abysi glycogen synthase (22), it is in a complex with the antagonistic drug elagolix, and remains in inactive conformation in respect to G protein coupling.
+GnRH1R has the overall architecture of seven canonical transmembrane (TM) helices with connecting extra- and intracellular loop domains (ECL/ICL) similar to [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin like receptors]. However, it lacks the typically occurring cytoplasmic C-terminal helix and has an unusual ligand binding mode. The structural variation between existing GnRHR Typ I, II and III in different species has been analyzed <ref>DOI: 10.1210/er.2003-0002</ref>. First crystallographic structure analysis of human GnGH1R serve the investigation of the molecular mechanism of the receptor <ref> DOI: 10.1038/s41467-020-19109-w>. In this analysis the GnRH1R contains certain modifications: ICL3 (aa 243-256) is replaced by the Pyrococcus abysi glycogen synthase (22), it is in a complex with the antagonistic drug elagolix, and remains in inactive conformation in respect to G protein coupling.
 In this conformation, an intrahelical salt bridge is observed between D1383.49 and R1393.50, as well as a polar interaction between R139 3.50 and T265 6.33 (This restricts the outward movement of those TMs associated with GPCR activation).
 The ECL2 of GnRH1R forms an extended β-hairpin and is anchored to the extracellular tip of TM3 through a conserved disulﬁde bond between residues C1143.25 and C196 in ECL2.

Sandbox Reserved 1646

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Revision as of 10:56, 22 January 2021

Gonadotropin releasing hormone 1 receptor (GnRHR)

Contents

Biological Function

Disease

Relevance

Structure

General structure

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