Sandbox Reserved 1646

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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'>
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.
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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=== General structure ===
=== General structure ===
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GnRH1R has the overall architecture of <scene name='86/868179/Basic_structure/4'>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.
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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 ===

Current revision

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)

PDB ID 7BR3

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