engleski

Conformational study of Bacteroides thetaiotaomicron dipeptidyl peptidase III

Dipeptidyl peptidase III isolated from Bacteroides thetaiotaomicron is a two-domain zinc exopeptidase from the M49 family. Members of this family, characterized by their HEXXGH motive, cleave dipeptidyl residues from the N-terminus of their substrates. This conserved region contains two His residues that coordinate the Zn ion along with Glu449 and Glu476. The BtDPP3 crystal structure shows two domains separated by a cleft, strongly resembling the human DPP3 despite the low sequence identity (~23%). In this work we used classical and accelerated MD to examine the long-range conformational changes of the enzyme over the course of 200 ns and compared them to its human counterpart. In order to determine the best method for the enzyme and complex description, a side-by-side comparison of ff03, ff12SB and ff14SB was performed. After the identification of significant (open and closed) conformations, syntetic substrates Arg-Arg-2-naphtylamide and Lys-Ala-2-naphtylamide were docked into the active site in order to understand enzyme-ligand interactions. Special emphasis has been placed on the zinc ion coordination flexibility, since the existing data for human DPP3 suggests the high plasticity of the Zn2+ coordination.

dipeptidyl peptidase III ; computational ; docking

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