Abstract:The human genome encodes six proteins of family 18 glycosyl hydrolases, two active chitinases and four chitinase-like lectins (chilectins) lacking catalytic activity. The present article is dedicated to homology modeling of 3D structure of human chitinase 3-like 2 protein (CHI3L2), which is overexpressed in glial brain tumors, and its structural comparison with homologous chi-lectin CHI3L1. Two crystal structures of CHI3L1 in free state (Protein Data Bank codes 1HJX and 1NWR) were used as structural templates for the homology modeling by Modeller 9.7 program, and the best quality model structure was selected from the obtained model ensemble.Analysis of potential oligosaccharide-binding groove structures of CHI3L1 and CHI3L2 revealed significant differences between these two homologous proteins. . The differences between these residues could influence the structure of the ligand-binding groove and substantially change the ability of CHI3L2 to bind oligosaccharide ligands. © Versita Sp. z o.o.
Cytoplasmic tyrosyl-tRNA synthetase (TyrRS) is one of the key enzymes of protein biosynthesis. TyrRSs of pathogenic organisms have gained attention as potential targets for drug development. Identifying structural differences between various TyrRSs will facilitate the development of specific inhibitors for the TyrRSs of pathogenic organisms. However, there is a deficiency in structural data for mammalian cytoplasmic TyrRS in complexes with substrates. In this work, we constructed spatial structure of full-length Bos taurus TyrRS (BtTyrRS) and its complexes with substrates using the set of computational modeling techniques. Special attention was paid to BtTyrRS complexes with substrates [L-tyrosine, K and ATP:Mg] and intermediate products [tyrosyl-adenylate (Tyr-AMP), K and PP:Mg] with the different catalytic loop conformations. In order to analyze their dynamical properties, we performed 100 ns of molecular dynamics (MD) simulations. MD simulations revealed new structural data concerning the tyrosine activation reaction in mammalian TyrRS. Formation of strong interaction between Lys154 and γ-phosphate suggests the additional role of CP1 insertion as an important factor for ATP binding. The presence of a potassium-binding pocket within the active site of mammalian TyrRS compensates the absence of the second lysine in the KMSKS motif. Our data provide new details concerning a role of K ions at different stages of the first step of the tyrosylation reaction, including the coordination of substrates and involvement in the PP releasing. The results of this work suggest that differences between ATP-binding sites of mammalian and bacterial TyrRSs are meaningful and could be exploited in the drug design.
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