In collaboration with Jinpeng Sun/Xiao Yu from Shandong University, Zhenhua Shao/ Wei Yan's research team at the State Key Laboratory of Biotherapy of West China Hospital (WCH) published their latest research findings "Ligand Recognition and G Protein Coupling of Trace Amine-Associated Receptor TAAR1" in Nature on November 7th. The West China Hospital is the first work unit and the first communication unit of this project. Zheng Xu, Siyuan Shen, postdoctoral fellows from WCH, and doctoral students Jing Jing Yu, Chao Wu, and Chang Zhao are the co first authors of this article (a total of 7 people). Zhenhua Shao and Wei Yan are the co corresponding authors.
This study is the first of its kind to characterize the pharmacology and molecular mechanisms of the clinically important psychiatric drug target TAAR1. Researchers discovered the plasticity of drug recognition pockets in the TAAR1 receptor. Based on the new mechanism, they screened and obtained new ligands targeting TAAR1, providing a very important theoretical basis for drug development targeting TAAR1.
“Trace amine-associated receptors (TAARs), a group of biogenic amine receptors, play pivotal roles in neurological and metabolic homeostasis. They recognize diverse endogenous trace amines (ETAs) and subsequently activate a range of G protein subtype signaling pathways. Notably, TAAR1 has emerged as a promising therapeutic target for treating psychiatric. However, the molecular mechanisms underlying its ability to recognize different ligands remain largely elusive. Here, we present nine cryo-electron microscopy (EM) structures, with eight showing human and mouse TAAR1 in complex with an array of ligands, including the endogenous 3-iodothyronamine, two antipsychotic agents, the psychoactive drug amphetamine, and two identified catecholamine agonists, and one depicting 5-HT1AR in complex with an antipsychotic agent. These structures reveal a rigid consensus binding motif in TAAR1 that binds to ETAs stimuli and two extended binding pockets that accommodate diverse chemotypes. Combined with mutational analysis, functional assays and molecular dynamic simulations, we elucidate the structural basis of drug polypharmacology and identify the species-specific differences between human and mouse TAAR1. Our study provides insights into the mechanism of ligand recognition and G protein selectivity by TAAR1, which may aid the discovery of ligands or therapeutic strategies for neurological and metabolic disorders.”(Abstract)
Figure. Pharmacology and molecular mechanism of TAAR1, a schematic diagram of TAAR1 responding to downstream G protein signaling mediated by different ligand activations. b. TAAR1 diverse ligand structure. c. Diverse biogenic amines activate the G protein signaling of human TAAR1 (hTAAR1) and mouse TAAR1 (mTAAR1). d. The ligand recognition pocket of TAAR1 has plasticity. e. The molecular mechanism by which SEP-363856 activates hTAAR1 and 5-HT1AR.
In summary, this study reveals the pharmacological mechanism of TAAR1 from multiple dimensions, which has guiding significance for the development of innovative drugs for major chronic diseases such as schizophrenia and depression in the future.
Source: https://www.nature.com/articles/s41586-023-06804-z
