n(alpha)-phosphorylalanylproline and benzamidine

Pit viper venoms contain a number of serine proteinases that exhibit one or more thrombin-like activities on fibrinogen and platelets, this being the case for the kinin-releasing and fibrinogen-clotting KN-BJ from the venom of Bothrops jararaca. A three-dimensional structural model of the KN-BJ2 serine proteinase was built by homology modeling using the snake venom plasminogen activator TSV-PA as a major template and porcine kallikrein as additional structural support. A set of intrinsic buried waters was included in the model and its behavior under dynamic conditions was molecular dynamics simulated, revealing a most interesting similarity pattern to kallikrein. The benzamidine-based thrombin inhibitors alpha-NAPAP, 3-TAPAP, and 4-TAPAP were docked into the refined model, allowing for a more insightful functional characterization of the enzyme and a better understanding of the reported comparatively low affinity of KN-BJ2 toward those inhibitors.

Topics: Amidines; Amino Acid Sequence; Animals; Benzamidines; Binding Sites; Bothrops; Crotalid Venoms; Dipeptides; Glycoproteins; Kallikreins; Models, Molecular; Molecular Sequence Data; Piperidines; Protein Conformation; Sequence Homology, Amino Acid; Serine Endopeptidases; Serine Proteinase Inhibitors; Static Electricity; Structural Homology, Protein; Thrombin; Water