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The results were published in cell

Recently, the team of Professor Lei Zhang from the School of Physics of Xi’an Jiaotong University has cooperated with Sichuan University, Shandong University, National Protein Center (Shanghai), Chinese University of Hong Kong, and other units to use cryo-electron microscopy technology to make significant progress in the regulation of dopamine receptors.

 

As a neurotransmitter that can please people, dopamine plays an important role in the treatment of central nervous system diseases and can regulate various physiological processes such as addiction, memory, reward, metabolism, and hormone secretion. At present, it is known that dopamine receptors include two sub-families of D1 and D2. Among them, D1 receptors (DRD1 and DRD5) regulate central nervous system reward and exercise by activating Gs/Golf and stimulating the production of cyclic adenosine monophosphate (cAMP). And cognition, and play a beneficial role in inhibiting inflammation in peripheral tissues and maintaining cardiovascular and renal dynamic balance; D2 receptors (including DRD2, DRD3, and DRD4) are coupled with Gi/Go to inhibit cAMP accumulation and regulation Different physiological effects.

 

The above five dopamine receptor subtypes have high sequence homology and recognize the same endogenous ligands. Although the current drug development for these five subtypes has made important progress, the difference between dopamine receptor subtypes The mechanisms of agonist recognition, ligand selectivity, receptor activation, and G protein selectivity remain to be clarified. So far, the molecular mechanism of the D2 receptor recognition antagonist ligand and the molecular mechanism of selective agonist Bromocriptine to activate the DRD2-Gi signal transduction complex have been revealed one after another. However, the structural basis of D1 subfamily recognition ligands is still lacking, which cannot provide a theoretical basis for the development of selective agonists, and thus cannot meet the clinical needs of highly selective agonists and other drugs for the treatment of Parkinson's disease and renal injury hypertension.

 

Using cryo-electron microscopy, the joint team analyzed for the first time that the DRD1-Gs complex was combined with catechol like agonists (hypertensive Fenoldopam, full agonist A77636, and G protein biased agonist SKF83959) and non-catechol The phenolic (Non-catechol like) agonist PW0464 and the three-dimensional structure of near-atomic resolution combined with dopamine and the positive allosteric modulator LY3154207.

 

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This research has extensive influence on the ligand recognition, activation mechanism, and signal transduction selection of dopamine receptors. Its main findings include: revealing the mechanism by which the orthosteric binding pocket (OBP) of DRD1 recognizes the endogenous hormone dopamine and catechol agonist ligands; elucidating the binding of DRD1 non-catechol agonists Mode; reveals the structural and functional characteristics of the extended binding pocket (EBP) of DRD1; discovers the positive allosteric modulator (PAM) site of DRD1; proposes the coupling and selectivity of DRD1 to G protein The key residues.

 

In summary, the joint team used single-particle cryo-electron microscopy technology to analyze the complex structure of dopamine receptor DRD1 and G protein, thereby explaining in detail the ligand recognition, allosteric regulation, and coupling of DRD1 at the atomic level. The research will bring a new dawn to the drug development and treatment of diseases such as hypertension, Parkinson’s syndrome, and kidney injury.

 

The relevant results of this research were published online on "Cell" on February 10, 2021, under the title "Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes", and were selected as the cover article of the current issue. Among them, cryo-electron microscopy-related work was completed by Xi'an Jiaotong University, with Dr. Lu Jin, a Ph.D. student from the team of Professor Zhang Lei of Xi'an Jiaotong University, as the co-first author of the paper, and Professor Zhang Lei as the co-corresponding author. This work was funded by the National Natural Science Foundation of China, the Fundamental Scientific Research Funds for Central Universities, the Central University Construction of World-Class Universities (Disciplines), and the Special Development Guidance Program for Special Features, Xi’an Jiaotong University Young Talents Program, etc. The relevant characterization and testing have been analyzed and tested. The center soft material cryo-electron microscope and other platforms and large-scale equipment are strongly supported. The soft condensed matter physics research team of Xi’an Jiaotong University takes Professor Zhang Lei and Professor Zhang Shengli of the School of Physics as academic leaders. In the past three years, it has focused on the key mechanism of the structure and function of the microscopic material system in the water environment. It has been continuously in Science, Nature Communications, JACS, Advanced Functional More than 30 papers have been published in internationally renowned journals such as Materials, Signal Transduction and Targeted Therapy, and National Science Review.

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