The versatile binding landscape of the TAAR1 pocket for LSD and other antipsychotic drug molecules.
Cell reports – July 23, 2024
Source: PubMed
Summary
Scientists have decoded how a key brain receptor interacts with LSD and antipsychotic medications, revealing a remarkably adaptable binding site. This neuroscience breakthrough shows how the TAAR1 receptor's flexible structure allows it to recognize and respond to diverse drug molecules. The findings explain why certain medications affect mood and behavior, and provide a molecular blueprint for developing more effective treatments for addiction and psychiatric conditions.
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.