Sandbox Reserved 1646

It is a member of the seven-transmembrane, rhodopsin likeG-protein coupled receptor (GPCR) family^[1] and is activated by the peptide hormone gonadotropin-releasing hormone (GnRH) or the rhodopsin likesynthetic 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.

Every molecular model (atomic coordinate file) in the Protein Data Bank (PDB) has a unique accession or identification code. The PDB ID of GnRHR is : 7BR3.

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 correspond to the inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), MAPK, and adenyl cyclase pathways^[3].

Structure

General structure

GnRH1R has the overall architecture of with connecting extra- and intracellular loop domains (ECL/ICL) similar to rhodopsin-like receptors. The structure belongs to the numerous structures of GPCRs currently published^[4]. However, GnRH1R 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^[5]. First crystallographic structure analysis of human GnGH1R serves the investigation of the molecular mechanism of the receptor^[6]. In this analysis the GnRH1R contains certain modifications: ICL3 (aa 243-256) is replaced by the Pyrococcus abysi , it is in a complex with the antagonistic drug , and remains in inactive conformation in respect to G protein coupling. In this conformation, the ECL2 of GnRH1R forms an and is anchored to the extracellular tip of TM3 through a conserved disulfide bond between residues C114 and C196. Following structural highlights are different to receptors of this family: The well-known conserved D-R-Y motif is in fact the motif in GnRH1R. An intrahelical salt bridge is observed between D138 and R139, as well as a polar interaction between R139 and T265 (This interaction restricts the outward movement of those TMs associated with GPCR activation). The (aa 18–33) before TM1 is well folded and appears inserted into the orthostatic binding cavity.

This structure belongs to the numerous structures of GPCR currently published. The G-protein-coupled receptor (GPCR) superfamily comprises an estimated 600–1,000 members and is the largest known class of molecular targets with proven therapeutic value. They play an incredible role in a range of functions in the human body, and increased understanding of these receptors has greatly affected modern medicine. In fact, researchers estimate that between one-third and one-half of the marketed drugs act by binding to GPCRs.^[7]

Ligand binding

The overall pocket in GnRH1R is defined by the N terminus, TM2, TM3, TM5, TM6, and TM7, forming a highly with a few polar residues (D98, N102, K121, and N305) The orthosteric binding pocket of GnRH1R is solvent-accessible, appears relatively shallow and plasticity is indicated with respect to different ligands. Structural analysis provides the possibility to design orally deliverable small molecules with activity towards the receptor. A detailed interaction network for elagolix has been described^[8] in which the N-terminus, residue Y283 and a polar formed by residues D98 and K121 are of particular importance for ligand recognition.

Fits in cavity (contact to surrounding residues: N102, Q174, and F178 from TM2 and TM4) indicating a distinct roles in mediating binding of different ligands. However, it is not engaged in GnRH activation of wild-type GnRH1R.

Engaged in the ligand recognition and activation of GnRH1R29 together with Y284 and M125 are suggested to form the bottom wall.

Signal transduction

Conformational rearrangements of common microswitches^[9] are characteristically influenced by the unusual ligand recognition and the absence of the cytoplasmic C-terminal helix. The transition of different GPCR conformation states is known to be mediated by water molecules by rearranging the conserved hydrophilic network formed by conserved amino acids in different helices^[10][11].

Disease

A mutation or dysfunction of the receptor could cause diseases impacting the reproduction function. More generally, the dysfunction of the pathways involving GnRH and its receptor leads to endocrine pathologies called hypogonadism^[12]. It exits many types of hypogonadism but the one involving the mutation of the receptor is the idiopathic hypogonadotropic hypogonadism (IHH). In this case, the mutation leads to failure of detectable ligand binding causing the decreased efficiency of the inositol pathway and consequently leading to the decrease of the LH, FSH, and sex steroid secretions^[13].

Moreover, the activity of the pathways related to the receptor and its localization can cause cancer^[14].

Relevance

The main uses of the couple GnRH - GnRHR in the medical field is to cure hormone-dependent diseases and assisted reproductive techniques. For instance, an agonist of GnRH is used for fertility preservation as an alternative to cryopreservation^[15]. In addition it is a promising therapeutic target for the treatment of conditions including uterine fibroids^[16], endometriosis ^[17], and prostate cancer^[18].

GnRH agonists and antagonists also have promise as novel contraceptives. Indeed, concerning animals, the GnRH receptor could be a good target for contraception with a DNA vaccine^[19].

Besides, on pharmacological grounds, the primary indications for GnRH antagonists will be in any situation in which chemical gonadotropic hypophysectomy is required.

References

1. ↑ Stojilkovic SS, Reinhart J, Catt KJ. Gonadotropin-releasing hormone receptors: structure and signal transduction pathways. Endocr Rev. 1994 Aug;15(4):462-99. doi: 10.1210/edrv-15-4-462. PMID:7988482 doi:http://dx.doi.org/10.1210/edrv-15-4-462
2. ↑ Cheung LW, Wong AS. Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues. FEBS J. 2008 Nov;275(22):5479-95. doi: 10.1111/j.1742-4658.2008.06677.x. PMID:18959738 doi:http://dx.doi.org/10.1111/j.1742-4658.2008.06677.x
3. ↑ Aguilar-Rojas A, Huerta-Reyes M. Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review). Oncol Rep. 2009 Nov;22(5):981-90. doi: 10.3892/or_00000525. PMID:19787210 doi:http://dx.doi.org/10.3892/or_00000525
4. ↑ Congreve M, de Graaf C, Swain NA, Tate CG. Impact of GPCR Structures on Drug Discovery. Cell. 2020 Apr 2;181(1):81-91. doi: 10.1016/j.cell.2020.03.003. PMID:32243800 doi:http://dx.doi.org/10.1016/j.cell.2020.03.003
5. ↑ Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr Rev. 2004 Apr;25(2):235-75. doi: 10.1210/er.2003-0002. PMID:15082521 doi:http://dx.doi.org/10.1210/er.2003-0002
6. ↑ Yan W, Cheng L, Wang W, Wu C, Yang X, Du X, Ma L, Qi S, Wei Y, Lu Z, Yang S, Shao Z. Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode. Nat Commun. 2020 Oct 20;11(1):5287. doi: 10.1038/s41467-020-19109-w. PMID:33082324 doi:http://dx.doi.org/10.1038/s41467-020-19109-w
7. ↑ Katritch V, Cherezov V, Stevens RC. Structure-function of the G protein-coupled receptor superfamily. Annu Rev Pharmacol Toxicol. 2013;53:531-56. doi:, 10.1146/annurev-pharmtox-032112-135923. Epub 2012 Nov 8. PMID:23140243 doi:http://dx.doi.org/10.1146/annurev-pharmtox-032112-135923
8. ↑ Yan W, Cheng L, Wang W, Wu C, Yang X, Du X, Ma L, Qi S, Wei Y, Lu Z, Yang S, Shao Z. Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode. Nat Commun. 2020 Oct 20;11(1):5287. doi: 10.1038/s41467-020-19109-w. PMID:33082324 doi:http://dx.doi.org/10.1038/s41467-020-19109-w
9. ↑ Clark LD, Dikiy I, Chapman K, Rodstrom KE, Aramini J, LeVine MV, Khelashvili G, Rasmussen SG, Gardner KH, Rosenbaum DM. Ligand modulation of sidechain dynamics in a wild-type human GPCR. Elife. 2017 Oct 6;6. pii: 28505. doi: 10.7554/eLife.28505. PMID:28984574 doi:http://dx.doi.org/10.7554/eLife.28505
10. ↑ Venkatakrishnan AJ, Ma AK, Fonseca R, Latorraca NR, Kelly B, Betz RM, Asawa C, Kobilka BK, Dror RO. Diverse GPCRs exhibit conserved water networks for stabilization and activation. Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3288-3293. doi:, 10.1073/pnas.1809251116. Epub 2019 Feb 6. PMID:30728297 doi:http://dx.doi.org/10.1073/pnas.1809251116
11. ↑ Yan W, Cheng L, Wang W, Wu C, Yang X, Du X, Ma L, Qi S, Wei Y, Lu Z, Yang S, Shao Z. Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode. Nat Commun. 2020 Oct 20;11(1):5287. doi: 10.1038/s41467-020-19109-w. PMID:33082324 doi:http://dx.doi.org/10.1038/s41467-020-19109-w
12. ↑ Richard-Eaglin A. Male and Female Hypogonadism. Nurs Clin North Am. 2018 Sep;53(3):395-405. doi: 10.1016/j.cnur.2018.04.006. PMID:30100005 doi:http://dx.doi.org/10.1016/j.cnur.2018.04.006
13. ↑ Meysing AU, Kanasaki H, Bedecarrats GY, Acierno JS Jr, Conn PM, Martin KA, Seminara SB, Hall JE, Crowley WF Jr, Kaiser UB. GNRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone. J Clin Endocrinol Metab. 2004 Jul;89(7):3189-98. doi: 10.1210/jc.2003-031808. PMID:15240592 doi:http://dx.doi.org/10.1210/jc.2003-031808
14. ↑ Harrison GS, Wierman ME, Nett TM, Glode LM. Gonadotropin-releasing hormone and its receptor in normal and malignant cells. Endocr Relat Cancer. 2004 Dec;11(4):725-48. doi: 10.1677/erc.1.00777. PMID:15613448 doi:http://dx.doi.org/10.1677/erc.1.00777
15. ↑ Torrealday S, Lalioti MD, Guzeloglu-Kayisli O, Seli E. Characterization of the gonadotropin releasing hormone receptor (GnRHR) expression and activity in the female mouse ovary. Endocrinology. 2013 Oct;154(10):3877-87. doi: 10.1210/en.2013-1341. Epub 2013 Aug, 2. PMID:23913446 doi:http://dx.doi.org/10.1210/en.2013-1341
16. ↑ Ali M, Chaudhry ZT, Al-Hendy A. Successes and failures of uterine leiomyoma drug discovery. Expert Opin Drug Discov. 2018 Feb;13(2):169-177. doi:, 10.1080/17460441.2018.1417381. Epub 2017 Dec 18. PMID:29254389 doi:http://dx.doi.org/10.1080/17460441.2018.1417381
17. ↑ Perricos A, Wenzl R. Efficacy of elagolix in the treatment of endometriosis. Expert Opin Pharmacother. 2017 Sep;18(13):1391-1397. doi:, 10.1080/14656566.2017.1359258. Epub 2017 Jul 28. PMID:28737050 doi:http://dx.doi.org/10.1080/14656566.2017.1359258
18. ↑ Schally AV, Block NL, Rick FG. Discovery of LHRH and development of LHRH analogs for prostate cancer treatment. Prostate. 2017 Jun;77(9):1036-1054. doi: 10.1002/pros.23360. Epub 2017 Apr 27. PMID:28449236 doi:http://dx.doi.org/10.1002/pros.23360
19. ↑ Samoylov A, Napier I, Morrison N, Cochran A, Schemera B, Wright J, Cattley R, Samoylova T. DNA Vaccine Targeting Gonadotropin-Releasing Hormone Receptor and Its Application in Animal Contraception. Mol Biotechnol. 2019 Feb;61(2):73-83. doi: 10.1007/s12033-018-0137-9. PMID:30448908 doi:http://dx.doi.org/10.1007/s12033-018-0137-9