View source for 7vod


==Crystal structure of 5-HT2AR in complex with cariprazine==
<StructureSection load='7vod' size='340' side='right'caption='[[7vod]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VOD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VOD 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]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7RU:3-[4-[2-[4-[2,3-bis(chloranyl)phenyl]piperazin-1-yl]ethyl]cyclohexyl]-1,1-dimethyl-urea'>7RU</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7vod FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vod OCA], [https://pdbe.org/7vod PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vod RCSB], [https://www.ebi.ac.uk/pdbsum/7vod PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vod ProSAT]</span></td></tr>
</table>
<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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7vod" style="background-color:#fffaf0;"></div>

==See Also==
*[[5-hydroxytryptamine receptor 3D structures|5-hydroxytryptamine receptor 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Chen Z]]
[[Category: Cheng J]]
[[Category: Fan L]]
[[Category: Liu Z]]
[[Category: Lu D]]
[[Category: Luo Z]]
[[Category: Nie F]]
[[Category: Qi J]]
[[Category: Wang H]]
[[Category: Wang S]]
[[Category: Yu J]]