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The | ==Structure of the human class C GPCR metabotropic glutamate receptor 5 transmembrane domain in complex with the negative allosteric modulator 3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile== | ||
<StructureSection load='5cgc' size='340' side='right'caption='[[5cgc]], [[Resolution|resolution]] 3.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5cgc]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_virus_T4 Escherichia virus T4] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CGC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CGC FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.101Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=51D:3-CHLORO-4-FLUORO-5-[6-(1H-PYRAZOL-1-YL)PYRIMIDIN-4-YL]BENZONITRILE'>51D</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5cgc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cgc OCA], [https://pdbe.org/5cgc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cgc RCSB], [https://www.ebi.ac.uk/pdbsum/5cgc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cgc ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/ENLYS_BPT4 ENLYS_BPT4] Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.<ref>PMID:22389108</ref> [https://www.uniprot.org/uniprot/GRM5_HUMAN GRM5_HUMAN] Receptor for glutamate. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Fragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 22, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 22 and another molecule in the series, 11, were determined at resolutions of 2.6A and 3.1A respectively. | |||
Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 negative allosteric modulator HTL14242 (3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile).,Christopher J, Aves SJ, Bennett KA, Dore AS, Errey JC, Jazayeri A, Marshall FH, Okrasa K, Serrano-Vega MJ, Tehan B, Wiggin GR, Congreve M J Med Chem. 2015 Jul 30. PMID:26225459<ref>PMID:26225459</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 5cgc" style="background-color:#fffaf0;"></div> | ||
[[Category: Aves | |||
[[Category: | ==See Also== | ||
[[Category: Christopher | *[[Metabotropic glutamate receptor 3D structures|Metabotropic glutamate receptor 3D structures]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: Jazayeri | </StructureSection> | ||
[[Category: | [[Category: Escherichia virus T4]] | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Aves SJ]] | ||
[[Category: Bennett KA]] | |||
[[Category: Christopher JA]] | |||
[[Category: Congreve M]] | |||
[[Category: Dore AS]] | |||
[[Category: Errey JC]] | |||
[[Category: Jazayeri A]] | |||
[[Category: Marshall FH]] | |||
[[Category: Okrasa K]] | |||
[[Category: Serrano-Vega MJ]] | |||
[[Category: Tehan BG]] | |||
[[Category: Wiggin GR]] | |||
Latest revision as of 14:20, 10 January 2024
Structure of the human class C GPCR metabotropic glutamate receptor 5 transmembrane domain in complex with the negative allosteric modulator 3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrileStructure of the human class C GPCR metabotropic glutamate receptor 5 transmembrane domain in complex with the negative allosteric modulator 3-chloro-4-fluoro-5-[6-(1H-pyrazol-1-yl)pyrimidin-4-yl]benzonitrile
Structural highlights
FunctionENLYS_BPT4 Endolysin with lysozyme activity that degrades host peptidoglycans and participates with the holin and spanin proteins in the sequential events which lead to the programmed host cell lysis releasing the mature viral particles. Once the holin has permeabilized the host cell membrane, the endolysin can reach the periplasm and break down the peptidoglycan layer.[1] GRM5_HUMAN Receptor for glutamate. The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system and generates a calcium-activated chloride current. Publication Abstract from PubMedFragment screening of a thermostabilized mGlu5 receptor using a high-concentration radioligand binding assay enabled the identification of moderate affinity, high ligand efficiency (LE) pyrimidine hit 5. Subsequent optimization using structure-based drug discovery methods led to the selection of 22, HTL14242, as an advanced lead compound for further development. Structures of the stabilized mGlu5 receptor complexed with 22 and another molecule in the series, 11, were determined at resolutions of 2.6A and 3.1A respectively. Fragment and Structure-Based Drug Discovery for a Class C GPCR: Discovery of the mGlu5 negative allosteric modulator HTL14242 (3-chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile).,Christopher J, Aves SJ, Bennett KA, Dore AS, Errey JC, Jazayeri A, Marshall FH, Okrasa K, Serrano-Vega MJ, Tehan B, Wiggin GR, Congreve M J Med Chem. 2015 Jul 30. PMID:26225459[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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