engleski

Bacteroides thetaiotaomicron dipeptidyl peptidase III complexes with synthetic substrates

Dipeptidyl peptidase III isolated from Bacteroides thetaiotaomicron is a two-domain zinc exopeptidase from the M49 family. Members of this family, characterized by HEXXGH and EEXR(K)AE(D) motifs, 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 performed docking of synthetic substrates Arg-Arg-2-naphtylamide and Lys-Ala-2-naphtylamide in the wild-type DPPIII and its C450S mutant in order to understand enzyme-ligand interactions. The starting structures were prepared from the human DPPIII-RRNA complex used in previous studies. Complex simulations were performed over the course of 200 ns using ff12sb and ff14sb force fields. These force fields were selected based on their good performance in conformational studies of both human and bacterial DPPIII. 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. Our results are in qualitative agreement with available kinetic data4 and represent a good starting point for further QM/MM studies necessary to elucidate the mechanism of the bacterial DPPIII.

DPP III ; dipeptidyl peptidase III ; docking

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