Sandbox Reserved 1646: Difference between revisions

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=== General structure ===

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 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.

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.

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.

Sandbox Reserved 1646: Difference between revisions

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@@ Line 13: / Line 13: @@
 === General structure ===
-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 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.
+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.
 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.