The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.
Cell reports July 23, 2024 Kexin Jiang, You Zheng, Liting Zeng et al. 12 citations
The 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.