engleski

Influence of ligands and protein binding to structure and flexybility of human dipeptidyl peptidase III

Dipeptidyl peptidase III (DPP III), the sole member of the M49 family of metallopeptidases, is a zinc-dependent exopeptidase which takes part in the intracellular protein metabolism. Human DPP III (h.DPP III) is also related to some pathophysiological processes like cataractogenesis, tumor growth and influenza virus infection. Nrf2-Keap1 signalling pathway is major regulator of cytoprotective responses to oxidative and electrophilic stress. High Nrf2 activity commonly occurs in cancer cells with adverse outcomes. Keap1 binds to Nrf2 and promotes its degradation. Hast et al. revealed that DPP III contributes to the activation of transcription factor Nrf2 by binding to its negative regulator, repressor protein, Keap1. In order to rationalize experimental data and better understand behaviour of human dipeptidyl peptidase III (h.DPP III) in physiological conditions we performed exhaustive in silico study of h.DPP III and its complexes with small ligands and Keap1. A range of molecular dynamics simulation techniques, conventional, accelerated and steered were used to investigate the h.DPP III conformational landscape and the influence of ligand binding on the protein structure and dynamics. According to the results, the compact forms of h.DPP III are more stable, but the open and partially closed states, spanning a wide range of conformations, can more effectively recognize the substrate which preferentially binds to the five-stranded ß-core of the lower DPP III domain. The simulations indicate the existence of a dynamic equilibrium between open and semi-closed states and revealed two ways that the protein can close, leading to two distinct compact structures. The simulations clearly indicate that the mode of closure is determined by presence of a ligand. Recently we have built the complex between h.DPP III and keltch domain of Keap1. According to preliminary simulations it seems that h.DPP III binds to the kelch domain via the flexible loop of the upper, catalytic domain containg an “ETGE” motif. It seems that presence of the partner protein hinders the DPP III transformation from the open to semi-closed form which was observed during its simulations in solvent. However, we expect to have more reliable data in about two to three months.

dipeptidyl peptidase III ; DPP III ; Keap1 ; oxidative stress

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