Molecular dynamics simulations on RORγt:insights into its functional agonism and inverse agonism  

作　　者：Cong-min Yuan Hai-hong Chen Nan-nan Sun Xiao-jun Ma Jun Xu Wei Fu 

机构地区：[1]Minhang Hospital and Department of Medicinal Chemistry at School of Pharmacy,Fudan University,201203 Shanghai,China

出　　处：《Acta Pharmacologica Sinica》2019年第11期1480-1489,共10页中国药理学报（英文版）

基　　金：grants from the National Natural Science Foundation of China(Nos.81473136 and 81773635);We thank Dr.Xiao-qin Huang from Rice University(Houston,TX 77005,USA)for great help and discussion about the overall research design and final writing of this work.

摘　　要：The retinoic acid receptor-related orphan receptor(ROR)γt receptor is a member of nuclear receptors,which is indispensable for the expression of pro-in?ammatory cytokine IL-17.RORγt has been established as a drug target to design and discover novel treatments for multiple in?ammatory and immunological diseases.It is important to elucidate the molecular mechanisms of how RORγt is activated by an agonist,and how the transcription function of RORγt is interrupted by an inverse agonist.In this study we performed molecular dynamics simulations on four different RORγt systems,i.e.,the apo protein,protein bound with agonist,protein bound with inverse agonist in the orthosteric-binding pocket,and protein bound with inverse agonist in the allosteric-binding pocket.We found that the orthosteric-binding pocket in the apo-form RORγt was mostly open,con?rming that apo-form RORγt was constitutively active and could be readily activated(ca.tens of nanoseconds scale).The tracked data from MD simulations supported that RORγt could be activated by an agonist binding at the orthosteric-binding pocket,because the bound agonist helped to enhance the triplet His479–Tyr502–Phe506 interactions and stabilized H12 structure.The stabilized H12 helped RORγt to form the protein-binding site,and therefore made the receptor ready to recruit a coactivator molecule.We also showed that transcription function of RORγt could be interrupted by the binding of inverse agonist at the orthosteric-binding pocket or at the allosteric-binding site.After the inverse agonist was bound,H12 either structurally collapsed,or reorientated to a different position,at which the presumed protein-binding site was not able to be formed.

关 键 词：RORΓT molecular dynamics simulation AGONISM inverse AGONISM PROTEIN-BINDING SITE orthosteric-binding pocket allosteric-binding SITE 

分 类 号：O17[理学—数学]