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Information × Registration Number 0213U000822, 0107U004938 , R & D reports Title Dynamical aspects of functioning of eukaryotic tyrosyl-tRNA synthetase and the study of mutations effects on the tRNA aminoacylation process and the formation of neurodegeneration diseases popup.stage_title Head Kornelyuk Alexandr, Registration Date 28-03-2013 Organization Institute of molecular biology & genetics popup.description2 The research theme devoted to the study of dynamic aspects of the human tyrosyl-tRNA synthetase. A computer simulation of the spatial structure of a full-size H.sapiens tyrosyl-tRNA synthetase was performed and the flexibility of intermodule linker was found, which probably plays an important role in the interdomain communication between the catalytic N-module and EMAP II-like C-module. Computer simulation of molecular dynamics of full size H.sapiens tyrosyl-tRNA synthetase in the time interval of 100 ns conducted in grid environment Ukrainian national grid. Detected moving conformation intermodule linker synthetase and forming dynamic elements of secondary structure. Data analysis of molecular dynamics of full size HsTyrRS showed that the formation of compact structure and interaction between the C-module and catalytic module which lead to asymmetric state of TyrRS dimer. Discovered 3 zones interfaces on the surface of the catalytic N-module: Tyr79-Leu89, Pro200-Tyr204, Lys335, Ser338 and Ala339. Based on the molecular dynamics simulations revealed the formation of hydrogen bonds between Arg93 residue of cytokine ELR-motif and residues Ala340 and Glu479 of C-module, previously theoretically predicted P.Schimmel. These data support the hypothesis that full-size HsTyrRS devoid of cytokine activity by screening cytokine ELR-motif in a compact structure. Computer simulation of molecular dynamics of mutant forms of tyrosyl-tRNA synthetase-related of neuropathy Charcot-Marie-Tooth (Gly41Arg, Glu196Lys, del153VKQV156 and Asp265Lys) was performed and identified four possible causes of the impact of mutations on the enzyme: 1. Growth stiffness dimerization interface in mutant forms TyrRS. The density of contact provided greater mutual adaptation of the contacting surfaces of the interface are affected by mutation. Since the binding of TyrRS tRNKTyr requires adaptive mobility intermodule interface TyrRS, in mutant forms of this adaptation is much more difficult with increasing stiffness interface. 2. Formation of antiparallel B-structural elements in unstructured region between the helixes H9 and H10 (SP1-insertion of the Rossman fold), which may lead to changes in interactions with other proteins or partner to nonspecific aggregation of mutant TyrRS. 3. Changing the dynamic properties of the unstructured catalytic loop 222KMSSSEE228 in mutant proteins dive Met223 in the protein globule occurs with lower probability and catalytic loop keeps high portability and disordered structure. 4. Changing the dynamic properties of disordered loop 275-290, which contains in its composition Trp283. Radically different dynamics of disordered loops in mutant TyrRS forms of neuropathy in Charcot-Marie-Tooth making it impossible for interaction with Trp283 anticodon tRNKTyr and thus correct work of tRNKTyr. Maps of correlation movements in mutant TyrRS forms with neuropathy Charcot-Marie-Tooth disorders collectively reflect movements in the area dimerization interface and the formation of new antiparallel B-structures between the helixes H9 and H10 in SP1-insertion of the Rossman fold. Computer simulation of molecular dynamics phosphorylated form TyrRS showed the formation of salt bridges between Lys244 and Sep345 and Sep358 and Lys246, which alter the structure of the intermodule linker to form the exposed loop that sterically prevents the binding of tRNA to tyrosyl-tRNA synthetase. With the molecular docking was shown that hydrophobic probe 1,8-ANS bound to SP1-insertion of the Rossman fold in all four mutants of TyrRS associated with neuropathy Charcot-Marie-Tooth. Mutations lead to local conformational changes in the SP1-insertion and the formation of new hydrophobic sites on the surface of the enzyme. Product Description popup.authors В. В. Микуляк Д. Б. Ковальський Д. М. Ложко К. О. Одинець Л. О. Андрійчук М.О. Кордиш О. В. Савицький О. Л. Дубровський Ю. Ю. Кондратюк popup.nrat_date 2020-04-02 Close