7voe
From Proteopedia
(Difference between revisions)
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==Crystal structure of 5-HT2AR in complex with aripiprazole== | ==Crystal structure of 5-HT2AR in complex with aripiprazole== | ||
| - | <StructureSection load='7voe' size='340' side='right'caption='[[7voe]]' scene=''> | + | <StructureSection load='7voe' size='340' side='right'caption='[[7voe]], [[Resolution|resolution]] 2.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VOE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VOE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7voe]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VOE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VOE FirstGlance]. <br> |
| - | </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=7voe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7voe OCA], [https://pdbe.org/7voe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7voe RCSB], [https://www.ebi.ac.uk/pdbsum/7voe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7voe ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=9SC:7-[4-[4-[2,3-bis(chloranyl)phenyl]piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one'>9SC</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OLC:(2R)-2,3-DIHYDROXYPROPYL+(9Z)-OCTADEC-9-ENOATE'>OLC</scene></td></tr> |
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7vod|7vod]]</div></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=7voe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7voe OCA], [https://pdbe.org/7voe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7voe RCSB], [https://www.ebi.ac.uk/pdbsum/7voe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7voe ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/5HT2A_HUMAN 5HT2A_HUMAN]] G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:18703043, PubMed:19057895). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors (PubMed:28129538). Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways (PubMed:28129538). Signaling activates phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores (PubMed:18703043, PubMed:28129538). Affects neural activity, perception, cognition and mood (PubMed:18297054). Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction.<ref>PMID:1330647</ref> <ref>PMID:18297054</ref> <ref>PMID:18703043</ref> <ref>PMID:19057895</ref> <ref>PMID:21645528</ref> <ref>PMID:22300836</ref> <ref>PMID:28129538</ref> (Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.<ref>PMID:24089568</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Partial agonist activity at the dopamine D2 receptor (DRD2) is a key feature of third-generation antipsychotics (TGAs). However, TGAs also act as antagonists or weak partial agonists to the serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HT2AR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HT2AR binding pocket, with secondary pharmacophores inserted in a similar way to a 'bolt'. This insight into the binding modes of TGAs offered a structural mechanism underlying their varied partial efficacies at 5-HT2AR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HT1AR with negligible 5-HT2AR binding that displayed potent antipsychotic-like activity without motor side effects in mice. This TGA lead also had antidepressant-like effects and improved cognitive performance in mouse models via 5-HT1AR. This work indicates that 5-HT2AR affinity is a dispensable contributor to the therapeutic actions of TGAs. | ||
| + | |||
| + | Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties.,Chen Z, Fan L, Wang H, Yu J, Lu D, Qi J, Nie F, Luo Z, Liu Z, Cheng J, Wang S Nat Neurosci. 2021 Dec 9. pii: 10.1038/s41593-021-00971-w. doi:, 10.1038/s41593-021-00971-w. PMID:34887590<ref>PMID:34887590</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7voe" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Chen Z]] | + | [[Category: Chen, Z]] |
| - | [[Category: Cheng J]] | + | [[Category: Cheng, J]] |
| - | [[Category: Fan L]] | + | [[Category: Fan, L]] |
| - | [[Category: Liu Z]] | + | [[Category: Liu, Z]] |
| - | [[Category: Lu D]] | + | [[Category: Lu, D]] |
| - | [[Category: Luo Z]] | + | [[Category: Luo, Z]] |
| - | [[Category: Nie F]] | + | [[Category: Nie, F]] |
| - | [[Category: Qi J]] | + | [[Category: Qi, J]] |
| - | [[Category: Wang H]] | + | [[Category: Wang, H]] |
| - | [[Category: Wang S]] | + | [[Category: Wang, S]] |
| - | [[Category: Yu J]] | + | [[Category: Yu, J]] |
| + | [[Category: Antipsychotic]] | ||
| + | [[Category: Aripiprazole]] | ||
| + | [[Category: Dopamine receptor]] | ||
| + | [[Category: Gpcr]] | ||
| + | [[Category: Membrane protein]] | ||
| + | [[Category: Serotonin receptor]] | ||
Revision as of 14:21, 29 December 2021
Crystal structure of 5-HT2AR in complex with aripiprazole
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Categories: Large Structures | Chen, Z | Cheng, J | Fan, L | Liu, Z | Lu, D | Luo, Z | Nie, F | Qi, J | Wang, H | Wang, S | Yu, J | Antipsychotic | Aripiprazole | Dopamine receptor | Gpcr | Membrane protein | Serotonin receptor
