The Structural Basis Of The Interaction Between P38? And Nur77 And A Drug Screening Targeting P38?

p38? is a mitogen-activated protein kinase(MAPK),and its signaling pathway is closely related to cell inflammation,cell apoptosis,cell differentiation,myocardial hypertrophy,as well as cell cycle,which makes p38a an attracting drug target.Nuclear receptors involve in cell growth,development,homeostasis,and other physiological activities.It plays a fundamental role in cancer,inflammation,metabolism,and proliferative diseases.Nur77 is a member of the nuclear receptor family.Previous studies showed that the interaction between p38? and Nur77 led to the attenuation of inflammatory response induced by LPS,but the specific mode of interaction remains to be investigated.This study aims to elucidate the structural basis of p38a-Nur77 interaction for the identification of novel drug target sites in p38a.In this thesis,we derived interacting peptides from Nur77-LBD,and used ITC to detect their interaction with Nur77-LBD polypeptide.The crystallization conditions of possible complex crystals were obtained.In a different approach,we expressed the purified 15N-labeled p38? protein and identified five interacting amino acid residues based on the changes to the NMR spectra after titration with unlabeled Nur77,which laid the foundation for the detailed characterization of the interaction between the two proteins.In this thesis,we also carried out drug screening with the p38? crystals,and identified two compounds that bound p38a,which provides a basis for drug development targeting p38a.