7VOD

Crystal structure of 5-HT2AR in complex with cariprazine

7VOD の概要

• エントリーDOI: 10.2210/pdb7vod/pdb
• 分子名称: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562, MAGNESIUM ION, CHOLESTEROL, ... (5 entities in total)
• 機能のキーワード: gpcr, dopamine receptor, serotonin receptor, cariprazine, antipsychotic, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44639.37

構造登録者

Chen, Z.,Fan, L.,Wang, H.,Yu, J.,Lu, D.,Qi, J.,Nie, F.,Luo, Z.,Liu, Z.,Cheng, J.,Wang, S. (登録日: 2021-10-13, 公開日: 2021-12-22, 最終更新日: 2024-11-06)

主引用文献

Chen, Z.,Fan, L.,Wang, H.,Yu, J.,Lu, D.,Qi, J.,Nie, F.,Luo, Z.,Liu, Z.,Cheng, J.,Wang, S.
Structure-based design of a novel third-generation antipsychotic drug lead with potential antidepressant properties.
Nat.Neurosci., 25:39-49, 2022

PubMed Abstract: Partial agonist activity at the dopamine D 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-HTR). Here we present the crystal structures of aripiprazole- and cariprazine-bound human 5-HTR. Both TGAs adopt an unexpected 'upside-down' pose in the 5-HTR 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-HTR and DRD2. These structures enabled the design of a partial agonist at DRD2/3 and 5-HTR with negligible 5-HTR 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-HTR. This work indicates that 5-HTR affinity is a dispensable contributor to the therapeutic actions of TGAs.

PubMed: 34887590
DOI: 10.1038/s41593-021-00971-w

実験手法

X-RAY DIFFRACTION (3.3 Å)