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The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules. | LitMetric

The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.

Cell Rep

iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Shanghai Clinical Research and Trial Center, Shanghai, China. Electronic address:

Published: July 2024

AI Article Synopsis

Article 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.

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Source
http://dx.doi.org/10.1016/j.celrep.2024.114505DOI Listing

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