Sandbox Reserved 1646

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Besides, 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, 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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== Structural highlights ==
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== General Structure ==
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<ref>doi: 10.1210/er.2003-0002</ref>
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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 (Structure5). 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.
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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).
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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.
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Following structural highlights are different to receptors of this family: The conserved D3.49-R3.50-Y3.51 motif is in fact the D3.49-R3.50-S3.51 motif in GnRH1R. The N-terminal region (aa 18–33) before TM1 is well folded and appears inserted into the orthostatic binding cavity.
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<scene name='86/868179/Test/1'>Test</scene>
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== Ligand binding ==
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</StructureSection>
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The overall pocket in GnRH1R is defined by the N terminus, TM2, TM3, TM5, TM6, and TM7, forming a highly hydrophobic binding site with a few polar residues (D982.61, N1022.65, K1213.32, and N3057.35
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The orthosteric binding pocket of GnRH1R is solvent-accessible, appears relatively shallow and a plasticity is indicated with respect to different ligands. Structural analysis provides the possibility to design orally deliverable small molecules with activity towards the receptor.
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A detailed interaction network for elagolix has been described (Structure1) in which The N-terminus, residue Y2836.51 and a polar interaction network formed by residues D982.61 and K1213.32 are of particular importance for ligand recognition.
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N terminus: fits in cavity (contact to surrounding ressiudues: N1022.65, Q1744.60, and F1784.64 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.
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Y2836.51: engaged in the ligand recognition and activation of GnRH1R29 together with Y2846.52 and M1253.36 are suggested to form the bottom wall
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== Signal transduction ==
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Conformational rearrangements of common microswitches38,39 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 helices43
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Different motifs have already 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 F2726.40 and Y3237.53.
== References ==
== References ==
<references/>
<references/>

Revision as of 12:12, 15 January 2021

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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