The Role of Conformational Dynamics and Allostery in the Control of Distinct Efficacies of Agonists to the Glucocorticoid Receptor

Frontiers in Molecular Biosciences

Mintao Xue¹  Jigang Fan²  Shu Cao³  Shaoyong Lu⁴  Yuxin Shi⁴  Duan Ni⁵ 

[1] Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China;Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China;Department of Urology, Ezhou Central Hospital, Hubei, China;Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China;The Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia;

关键词: glucocorticoid receptor;    allosteric communication;    allosteric site;    molecular dynamics simulation;    drug discovery;   

DOI  :  10.3389/fmolb.2022.933676

来源: DOAJ

【 摘 要 】

Glucocorticoid receptor (GR) regulates various cellular functions. Given its broad influence on metabolic activities, it has been the target of drug discovery for decades. However, how drugs induce conformational changes in GR has remained elusive. Herein, we used five GR agonists (dex, AZ938, pred, cor, and dibC) with different efficacies to investigate which aspect of the ligand induced the differences in efficacy. We performed molecular dynamics simulations on the five systems (dex-, AZ938-, pred-, cor-, and dibC-bound systems) and observed a distinct discrepancy in the conformation of the cofactor TIF2. Moreover, we discovered ligand-induced differences regarding the level of conformational changes posed by the binding of cofactor TIF2 and identified a pair of essential residues D590 and T39. We further found a positive correlation between the efficacies of ligands and the interaction of the two binding pockets’ domains, where D590 and T739 were involved, implying their significance in the participation of allosteric communication. Using community network analysis, two essential communities containing D590 and T739 were identified with their connectivity correlating to the efficacy of ligands. The potential communication pathways between these two residues were revealed. These results revealed the underlying mechanism of allosteric communication between the ligand-binding and cofactor-binding pockets and identified a pair of important residues in the allosteric communication pathway, which can serve as a guide for future drug discovery.

【 授权许可】

Unknown