7fee
From Proteopedia
(Difference between revisions)
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| - | ==Crystal | + | ==Crystal structure of the allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1== |
<StructureSection load='7fee' size='340' side='right'caption='[[7fee]], [[Resolution|resolution]] 2.70Å' scene=''> | <StructureSection load='7fee' size='340' side='right'caption='[[7fee]], [[Resolution|resolution]] 2.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7fee]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Pyrococcus_abyssi_GE5 Pyrococcus abyssi GE5]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7FEE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FEE FirstGlance]. <br> | <table><tr><td colspan='2'>[[7fee]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Pyrococcus_abyssi_GE5 Pyrococcus abyssi GE5]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7FEE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7FEE 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]] 2.7Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7Å</td></tr> | ||
| - | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7IC:6-methyl-3-[( | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7IC:6-methyl-3-[(1~{S})-2-nitro-1-thiophen-2-yl-ethyl]-2-phenyl-1~{H}-indole'>7IC</scene>, <scene name='pdbligand=9GF:5-(2-methyloctan-2-yl)-2-[(1~{R},2~{R},5~{R})-5-oxidanyl-2-(3-oxidanylpropyl)cyclohexyl]phenol'>9GF</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=OLA:OLEIC+ACID'>OLA</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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=7fee FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7fee OCA], [https://pdbe.org/7fee PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7fee RCSB], [https://www.ebi.ac.uk/pdbsum/7fee PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7fee ProSAT]</span></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=7fee FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7fee OCA], [https://pdbe.org/7fee PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7fee RCSB], [https://www.ebi.ac.uk/pdbsum/7fee PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7fee ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/Q9V2J8_PYRAB Q9V2J8_PYRAB] [https://www.uniprot.org/uniprot/CNR1_HUMAN CNR1_HUMAN] Involved in cannabinoid-induced CNS effects. Acts by inhibiting adenylate cyclase. Could be a receptor for anandamide. Inhibits L-type Ca(2+) channel current. Isoform 2 and isoform 3 have altered ligand binding.<ref>PMID:15620723</ref> | [https://www.uniprot.org/uniprot/Q9V2J8_PYRAB Q9V2J8_PYRAB] [https://www.uniprot.org/uniprot/CNR1_HUMAN CNR1_HUMAN] Involved in cannabinoid-induced CNS effects. Acts by inhibiting adenylate cyclase. Could be a receptor for anandamide. Inhibits L-type Ca(2+) channel current. Isoform 2 and isoform 3 have altered ligand binding.<ref>PMID:15620723</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Given the promising clinical value of allosteric modulators of G protein-coupled-receptors (GPCRs), mechanistic understanding of how these modulators alter GPCR function is of significance. Here, we report the crystallographic and cryo-electron microscopy structures of the cannabinoid receptor CB1 bound to the positive allosteric modulator (PAM) ZCZ011. These structures show that ZCZ011 binds to an extrahelical site in the transmembrane 2 (TM2)-TM3-TM4 surface. Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement is critical for the propagation of allosteric signals. ZCZ011 exerts a PAM effect by promoting TM2 rearrangement in favor of receptor activation and increasing the population of receptors that adopt an active conformation. In contrast, ORG27569, a negative allosteric modulator (NAM) of CB1, also binds to the TM2-TM3-TM4 surface and exerts a NAM effect by impeding the TM2 rearrangement. Our findings fill a gap in the understanding of CB1 allosteric regulation and could guide the rational design of CB1 allosteric modulators. | ||
| + | |||
| + | Molecular mechanism of allosteric modulation for the cannabinoid receptor CB1.,Yang X, Wang X, Xu Z, Wu C, Zhou Y, Wang Y, Lin G, Li K, Wu M, Xia A, Liu J, Cheng L, Zou J, Yan W, Shao Z, Yang S Nat Chem Biol. 2022 Aug;18(8):831-840. doi: 10.1038/s41589-022-01038-y. Epub 2022 , May 30. PMID:35637350<ref>PMID:35637350</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7fee" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Crystal structure of the allosteric modulator ZCZ011 binding to CP55940-bound cannabinoid receptor 1
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