7VOE
Crystal structure of 5-HT2AR in complex with aripiprazole
Summary for 7VOE
| Entry DOI | 10.2210/pdb7voe/pdb |
| Related | 7VOD |
| Descriptor | 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562, CHOLESTEROL, PENTAETHYLENE GLYCOL, ... (6 entities in total) |
| Functional Keywords | gpcr, dopamine receptor, serotonin receptor, aripiprazole, antipsychotic, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 1 |
| Total formula weight | 45255.16 |
| Authors | |
| Primary citation | 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 Cited by 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: 34887590DOI: 10.1038/s41593-021-00971-w PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
Download full validation report
