7wc8

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==Crystal structure of serotonin 2A receptor in complex with lumateperone==
==Crystal structure of serotonin 2A receptor in complex with lumateperone==
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<StructureSection load='7wc8' size='340' side='right'caption='[[7wc8]]' scene=''>
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<StructureSection load='7wc8' size='340' side='right'caption='[[7wc8]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WC8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WC8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[7wc8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WC8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WC8 FirstGlance]. <br>
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</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=7wc8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wc8 OCA], [https://pdbe.org/7wc8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wc8 RCSB], [https://www.ebi.ac.uk/pdbsum/7wc8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wc8 ProSAT]</span></td></tr>
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</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=92S:1-(4-fluorophenyl)-4-[(10~{R},15~{S})-4-methyl-1,4,12-triazatetracyclo[7.6.1.0^{5,16}.0^{10,15}]hexadeca-5,7,9(16)-trien-12-yl]butan-1-one'>92S</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>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7wc8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wc8 OCA], [https://pdbe.org/7wc8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wc8 RCSB], [https://www.ebi.ac.uk/pdbsum/7wc8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wc8 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR beta-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.
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Structure-based discovery of nonhallucinogenic psychedelic analogs.,Cao D, Yu J, Wang H, Luo Z, Liu X, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J, Wang S Science. 2022 Jan 28;375(6579):403-411. doi: 10.1126/science.abl8615. Epub 2022, Jan 27. PMID:35084960<ref>PMID:35084960</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 7wc8" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Cao D]]
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[[Category: Cao, D]]
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[[Category: Chen Z]]
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[[Category: Chen, Z]]
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[[Category: Cheng J]]
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[[Category: Cheng, J]]
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[[Category: Fan L]]
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[[Category: Fan, L]]
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[[Category: He L]]
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[[Category: He, L]]
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[[Category: Li J]]
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[[Category: Li, J]]
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[[Category: Liu X]]
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[[Category: Liu, X]]
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[[Category: Luo Z]]
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[[Category: Luo, Z]]
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[[Category: Qi J]]
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[[Category: Qi, J]]
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[[Category: Tang L]]
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[[Category: Tang, L]]
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[[Category: Wang H]]
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[[Category: Wang, H]]
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[[Category: Wang S]]
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[[Category: Wang, S]]
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[[Category: Yu J]]
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[[Category: Yu, J]]
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[[Category: 5-ht]]
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[[Category: Lumateperone]]
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[[Category: Membrane protein]]
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[[Category: Serotonin]]
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[[Category: Serotonin 2a receptor]]

Revision as of 11:16, 16 February 2022

Crystal structure of serotonin 2A receptor in complex with lumateperone

PDB ID 7wc8

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