7vod

Crystal structure of 5-HT2AR in complex with cariprazine

spinqualitylabelsall models 7vod, resolution 3.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.3Å Ligands: 7RU, CLR, MG, OLC Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also 5-hydroxytryptamine receptor 3D structures

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