7WC8

Crystal structure of serotonin 2A receptor in complex with lumateperone

Summary for 7WC8

• Entry DOI: 10.2210/pdb7wc8/pdb
• Descriptor: 5-hydroxytryptamine receptor 2A,5-hydroxytryptamine receptor 2A,Soluble cytochrome b562, MAGNESIUM ION, CHOLESTEROL, ... (8 entities in total)
• Functional Keywords: serotonin 2a receptor, serotonin, 5-ht, membrane protein, lumateperone
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 48287.01

Authors

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. (deposition date: 2021-12-18, release date: 2022-01-26, Last modification date: 2024-11-13)

Primary citation

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.
Structure-based discovery of nonhallucinogenic psychedelic analogs.
Science, 375:403-411, 2022

PubMed Abstract: Drugs that target the human serotonin 2A receptor (5-HTR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HTR 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-HTR β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HTR 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.

PubMed: 35084960
DOI: 10.1126/science.abl8615

Experimental method

X-RAY DIFFRACTION (2.45 Å)