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==Gonadotropin releasing hormone 1 receptor (GnRHR) ==
==Gonadotropin releasing hormone 1 receptor (GnRHR) ==
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<StructureSection load='7BR3' size='340' side='right' caption='PDB ID 7BR3' scene=''>
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<StructureSection load='7BR3' size='340' side='right' caption='PDB ID 7BR3' scene='86/868179/Full_structure_helices/2'>
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It is a member of the seven-transmembrane, [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin like][https://en.wikipedia.org/wiki/G_protein-coupled_receptor G-protein coupled receptor (GPCR)] family<ref>DOI: 10.1210/edrv-15-4-462</ref> and is activated by the peptide hormone [https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone gonadotropin-releasing hormone (GnRH)] or the [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin like][https://proteopedia.org/wiki/index.php/4d5m synthetic agonist)]. The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate <ref>DOI: 10.1111/j.1742-4658.2008.06677.x</ref>. Its activity is critical for successful reproductive function. Several diseases are associated with a dysfunction of this receptor or the corresponding signaling cascade.
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It is a member of the seven-transmembrane, [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin like][https://en.wikipedia.org/wiki/G_protein-coupled_receptor G-protein coupled receptor (GPCR)] family<ref>DOI: 10.1210/edrv-15-4-462</ref> and is activated by the peptide hormone [https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone gonadotropin-releasing hormone (GnRH)] or the [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin like][https://proteopedia.org/wiki/index.php/4d5m synthetic agonist)]. The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate<ref>DOI: 10.1111/j.1742-4658.2008.06677.x</ref>. Its activity is critical for successful reproductive function. Several diseases are associated with a dysfunction of this receptor or the corresponding signaling cascade.
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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 : [https://www.rcsb.org/structure/7BR3 7BR3].
== Biological Function ==
== Biological Function ==
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The gonadotropin-releasing hormone 1 receptor is located in the plasmic membrane of [https://en.wikipedia.org/wiki/Gonadotropic_cell pituitary gonadotrope cells] in the anterior pituitary, a major organ of the [https://en.wikipedia.org/wiki/Endocrine_system endocrine system] in the brain. It is activated by the [https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone 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 [https://en.wikipedia.org/wiki/Luteinizing_hormone gonadotropic luteinizing hormone (LH)] and [https://en.wikipedia.org/wiki/Follicle-stimulating_hormone 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. <ref> DOI: 10.3892/or_00000525</ref>.
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The gonadotropin-releasing hormone 1 receptor is located in the plasmic membrane of [https://en.wikipedia.org/wiki/Gonadotropic_cell pituitary gonadotrope cells] in the anterior pituitary, a major organ of the [https://en.wikipedia.org/wiki/Endocrine_system endocrine system] in the brain. It is activated by the [https://en.wikipedia.org/wiki/Gonadotropin-releasing_hormone 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 [https://en.wikipedia.org/wiki/Luteinizing_hormone gonadotropic luteinizing hormone (LH)] and [https://en.wikipedia.org/wiki/Follicle-stimulating_hormone 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<ref> DOI: 10.3892/or_00000525</ref>.
==Structure ==
==Structure ==
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=== General structure ===
=== General structure ===
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GnRH1R has the overall architecture of seven canonical transmembranes (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 serves the investigation of the molecular mechanism of the receptor<ref>DOI: 10.1038/s41467-020-19109-w</ref>. In this analysis the GnRH1R contains certain modifications: ICL3 (aa 243-256) is replaced by the ''Pyrococcus abysi'' <scene name='86/868179/Abysi_glycogen_synthase/1'>glycogen synthase</scene>, it is in a complex with the [https://en.wikipedia.org/wiki/Receptor_antagonist antagonistic] drug <scene name='86/868179/Elagolix/4'>elagolix</scene>, and remains in inactive conformation in respect to [https://en.wikipedia.org/wiki/G_protein G protein] coupling.
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GnRH1R has the overall architecture of <scene name='86/868179/Gnrh1_colored/7'>seven canonical transmembranes (TM) helices</scene> with connecting extra- and intracellular loop domains (ECL/ICL) similar to [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin-like receptors]. The structure belongs to the numerous structures of [https://en.wikipedia.org/wiki/G_protein-coupled_receptor GPCRs] currently published<ref>DOI: 10.1016/j.cell.2020.03.003</ref>. 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<ref>DOI: 10.1210/er.2003-0002</ref>. First crystallographic structure analysis of human GnGH1R serves the investigation of the molecular mechanism of the receptor<ref>DOI: 10.1038/s41467-020-19109-w</ref>. In this analysis the GnRH1R contains certain modifications: ICL3 (aa 243-256) is replaced by the ''Pyrococcus abysi'' <scene name='86/868179/Abysi_glycogen_synthase/3'>glycogen synthase</scene>, it is in a complex with the [https://en.wikipedia.org/wiki/Receptor_antagonist antagonistic] drug <scene name='86/868179/Elagolix/4'>elagolix</scene>, and remains in inactive conformation in respect to [https://en.wikipedia.org/wiki/G_protein G protein] coupling.
In this conformation, the ECL2 of GnRH1R forms an <scene name='86/868179/Beta-hairpin_structure/2'>extended β-hairpin</scene> and is anchored to the extracellular tip of TM3 through a conserved disulfide bond between residues C114 and C196.
In this conformation, the ECL2 of GnRH1R forms an <scene name='86/868179/Beta-hairpin_structure/2'>extended β-hairpin</scene> 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 <scene name='86/868179/D-r-s_motif/2'>D138-R139-S140</scene> motif in GnRH1R. An intrahelical [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular 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 <scene name='86/868179/N-terminus/6'>N-terminal region</scene> (aa 18–33) before TM1 is well folded and appears inserted into the orthostatic binding cavity.
Following structural highlights are different to receptors of this family: The well-known conserved D-R-Y motif is in fact the <scene name='86/868179/D-r-s_motif/2'>D138-R139-S140</scene> motif in GnRH1R. An intrahelical [https://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular 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 <scene name='86/868179/N-terminus/6'>N-terminal region</scene> (aa 18–33) before TM1 is well folded and appears inserted into the orthostatic binding cavity.
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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.<ref>DOI:10.1186/1471-2105-9-363</ref>
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=== Ligand binding ===
=== Ligand binding ===
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Conformational rearrangements of common microswitches<ref>DOI: 10.7554/eLife.28505</ref> are characteristically influenced by the unusual ligand recognition and the absence of the cytoplasmic C-terminal helix.
Conformational rearrangements of common microswitches<ref>DOI: 10.7554/eLife.28505</ref> are characteristically influenced by the unusual ligand recognition and the absence of the cytoplasmic C-terminal helix.
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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<ref>DOI: 10.1073/pnas.1809251116</ref>.
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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<ref>DOI: 10.1073/pnas.1809251116</ref><ref>DOI: 10.1038/s41467-020-19109-w</ref>.
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Different motifs have been identified to be critical for signal transmission in GnH1R. Noteworthy, the hydrophobic Y6.51-Y6.52(TM6)-W6.48-F6.44 motif in TM6 and residues F272 and Y323<ref>DOI: 10.1038/s41467-020-19109-w</ref>.
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==Gonadotropin releasing hormone==
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===Hormone===
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GnRH is a decapeptide that was isolated and characterized by the groups of A V Schally and R C L Guillemin, the 1977 Nobel laureates.
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GnRH is the pivotal hypothalamic hormone regulating reproduction. Over 20 forms of the decapeptide have been identified in which the NH2- and COOH-terminal sequences, which are essential for receptor binding and activation, are conserved.
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In most vertebrates, there are at least two, and usually three, forms of GnRH. In mammals, there are two forms, GnRH I which regulates gonadotropin, and GnRH II which appears to be a neuromodulator and stimulates sexual behavior.
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===Antagonist===
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Like GnRH, peptide antagonists of the GnRH receptor are decapeptides, but with 50–70% of amino acids substituted, and they exhibit classical competitive antagonism ;
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Blockade of GnRH effects may be wanted for a variety of reasons—eg, to prevent untimely luteinization during assisted reproduction or in the treatment of sex-hormone-dependent disorders
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Unlike the agonists, GnRH antagonists do not induce an initial stimulation of gonadotropin release but cause an immediate and rapid, reversible suppression of gonadotropin secretion. The principal mechanism of action of GnRH antagonists is competitive receptor occupancy of GnRH-r. <ref>DOI: 10.1016/S0140-6736(01)06797-6</ref>
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== Disease ==
== Disease ==
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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 [https://en.wikipedia.org/wiki/Hypogonadism hypogonadism]. <ref> DOI: 10.1016/j.cnur.2018.04.006</ref> It exits many types of hypogonadism but the one involving the mutation of the receptor is the [https://en.wikipedia.org/wiki/Isolated_hypogonadotropic_hypogonadism 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 <ref>DOI 10.1210/jc.2003-031808</ref>.
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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 [https://en.wikipedia.org/wiki/Hypogonadism hypogonadism]<ref> DOI: 10.1016/j.cnur.2018.04.006</ref>. It exits many types of hypogonadism but the one involving the mutation of the receptor is the [https://en.wikipedia.org/wiki/Isolated_hypogonadotropic_hypogonadism 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<ref>DOI 10.1210/jc.2003-031808</ref>.
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Moreover, the activity of the pathways related to the receptor and its localization can cause cancer. <ref>DOI: 10.1677/erc.1.00777</ref>
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Moreover, the activity of the pathways related to the receptor and its localization can cause cancer<ref>DOI: 10.1677/erc.1.00777</ref>.
== Relevance ==
== Relevance ==
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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 <ref>DOI 10.1210/en.2013-1341</ref>. In addition it is a promising therapeutic target for the treatment of conditions including uterine fibroids <ref>DOI: 10.1080/17460441.2018.1417381</ref>, endometriosis <ref>DOI: 10.1080/14656566.2017.1359258</ref>, and prostate cancer <ref>DOI: 10.1002/pros.23360</ref>.
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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<ref>DOI 10.1210/en.2013-1341</ref>. In addition it is a promising therapeutic target for the treatment of conditions including uterine fibroids<ref>DOI: 10.1080/17460441.2018.1417381</ref>, endometriosis <ref>DOI: 10.1080/14656566.2017.1359258</ref>, and prostate cancer<ref>DOI: 10.1002/pros.23360</ref>.
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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 <ref>DOI: 10.1007/s12033-018-0137-9</ref>
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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<ref>DOI: 10.1007/s12033-018-0137-9</ref>.
Besides, on pharmacological grounds, the primary indications for GnRH antagonists will be in any situation in which chemical gonadotropic hypophysectomy is required.
Besides, on pharmacological grounds, the primary indications for GnRH antagonists will be in any situation in which chemical gonadotropic hypophysectomy is required.

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Gonadotropin releasing hormone 1 receptor (GnRHR)

PDB ID 7BR3

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