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
Affiliations
Kexin Jiang
iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China
You Zheng
iHuman Institute, ShanghaiTech University, Shanghai, China
Liting Zeng
iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China
Ling Wang
iHuman Institute, ShanghaiTech University, Shanghai, China
Fei Li
iHuman Institute, ShanghaiTech University, Shanghai, China
Jun Pu
Department of Neurosurgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, China
Yingli Lu
Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Suwen Zhao
iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Corresponding author
Fei Xu
iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China; Shanghai Clinical Research and Trial Center, Shanghai, China; Corresponding author
Summary: 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.
