STUDY OF THE NK CELL RECEPTOR INTERACTION WITH THEIR COGNATE LIGANDS AND THEIR ROLE IN CANCER THERAPY

Abstract

Natural killer (NK) cells destroy virus-infected and tumor cells without prior antigen stimulation. The NK cell cytotoxicity is regulated largely by the expression of NK cell receptors that are able to bind major histocompatibility complex (MHC) class I glycoproteins. NK cells also express lysis triggering receptors specific for non-MHC ligands, including NKp30, NKp44, NKp46 and CD16. However, the nature of their ligands, recognized on target cells, is undefined. The activating receptors play a key role in activating the NK cells by specifically binding the activating ligands. The study conducted here deals with finding out activating ligands from tumor antigen database. It employs a computational approach to determine the binding pattern of NKp30 complexed with ligand B7H6 [PDB ID=3PV6] and finding out structural homologue of the ligand from tumor antigen database (T-Antigen Database). The homologues obtained were then subjected to molecular docking using HADDOCK web server. The ligand complexed with NKp30 showing lowest binding energy (energetically favorable) was simulated using Molecular Dynamics simulations to determine its stability in dynamic bodily conditions. The study also deals with finding the binding site of hemagglutinnin with NKp44 and NKp46. Experimental studies have already proven hemagglutinnin to be the activating ligand of NKp44 and NKp46 but due to lack of information of the binding site involved, further studies have been restricted. The study also presents the structural aspect of HLA-G and KIR2Dl4 interaction and the comparison of the binding affinity of KIR2DL4 with other class I HLA molecules- HLA-E, HLA-Cw3 and HLA-Cw4. The reliability of experimental procedure employed here has been validated by showing higher binding affinity of KIR2DL4 with HLA-G and lower binding efficiency with HLA-E, as reported by some previous studies. Residues of KIR2DL4, important for interactions, have also been explored. The study also revealed a greater binding efficiency of HLA-Cw3 and Cw4 with KIR2DL4, suggesting some unexplored role of KIR2DL4.