The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.
Kexin Jiang, You Zheng, Liting Zeng, Ling Wang, Fei Li, Jun Pu, Yingli Lu, Suwen Zhao, Fei Xu
Cell reports July 23, 2024 DOI: 10.1016/j.celrep.2024.114505 via PubMed
Summary
AI-generated from the abstractThe trace amine-associated receptor 1 (TAAR1) plays a key role in the signaling of the hallucinogen LSD and several antipsychotic drugs. This work presents the molecular structures of the TAAR1-Gs protein complex bound to LSD and to the partial agonist RO5263397, a drug candidate for schizophrenia and addiction. Through mutagenesis, functional studies, and molecular dynamics simulations, the authors describe a versatile binding pocket in TAAR1 that adapts to recognize different ligands, including in the ligand-free state. These results clarify cross-species recognition and partial activation of TAAR1, providing a structural basis for designing new antipsychotic medications.
Study at a glance
| Characteristics | Structural biology study with mutagenesis, functional studies, and molecular dynamics simulations Peer reviewed |
|---|---|
| Keywords | Cp: neuroscience Psychiatric medications Neuroreceptors Psychopharmacology psychotropic drugs Biochemistry |
| Citations | 12 |
| Key finding | The TAAR1 receptor has a highly adaptable binding pocket that recognizes diverse ligands, including LSD and the drug candidate RO5263397, revealing structural insights for antipsychotic drug design. |
Abstract
Increasing global concerns about psychoactive substance addiction and psychotic disorders highlight the need for comprehensive research into the structure-function relationship governing ligand recognition between these substances and their receptors in the brain. Recent studies indicate the significant involvement of trace amine-associated receptor 1 (TAAR1) in the signaling regulation of the hallucinogen lysergic acid diethylamide (LSD) and other antipsychotic drugs. This study presents structures of the TAAR1-Gs protein complex recognizing LSD, which exhibits a polypharmacological profile, and the partial agonist RO5263397, which is a drug candidate for schizophrenia and addiction. Moreover, we elucidate the cross-species recognition and partial activation mechanism for TAAR1, which holds promising implications from a drug discovery perspective. Through mutagenesis, functional studies, and molecular dynamics (MD) simulations, we provide a comprehensive understanding of a versatile TAAR1 pocket in recognizing various ligands as well as in the ligand-free state, underpinning the structural basis of its high adaptability. These findings offer valuable insights for the design of antipsychotic drugs.