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

  • Cell Rep. 2024 Jul 23;43(7):114505. doi: 10.1016/j.celrep.2024.114505.
Kexin Jiang  1 ,  You Zheng  2 ,  Liting Zeng  1 ,  Ling Wang  2 ,  Fei Li  2 ,  Jun Pu  3 ,  Yingli Lu  4 ,  Suwen Zhao  5 ,  Fei Xu  6
Affiliations
  • 1. iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 2. iHuman Institute, ShanghaiTech University, Shanghai, China.
  • 3. Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 4. Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5. iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: [email protected].
  • 6. 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: [email protected].
PMID: 39002128 DOI: 10.1016/j.celrep.2024.114505
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.

Keywords
CP: Neuroscience.
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