On the modeling of snake venom serine proteinase interactions with benzamidine-based thrombin inhibitors.
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.
Henriques
Elsa S
ES
REQUIMTE, Departamento de Química, Faculdade de Ciências do Porto, R. Campo Alegre, 687, 4169-007 Porto, Portugal.
Fonseca
Nelson
N
Ramos
Maria João
MJ
D000578:Amidines / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001550:Benzamidines / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D017837:Bothrops; D003435:Crotalid Venoms / Q000737:chemistry* / Q000378:metabolism*; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism; D007610:Kallikreins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D040681:Structural Homology, Protein; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014867:Water
D000578:Amidines; D001550:Benzamidines; D003435:Crotalid Venoms; D004151:Dipeptides; D006023:Glycoproteins; D010880:Piperidines; D015842:Serine Proteinase Inhibitors; D014867:Water; C028249:N(alpha)-phosphorylalanylproline; C070567:N(alpha)-(4-toluenesulfonyl)-4-amidinophenylalanylpiperidine; C070566:N(alpha)-(4-toluenesulfonyl)-3-amidinophenylalanylpiperidine; C499432:KN-BJ2 protein, Bothrops jararaca; D007610:Kallikreins; D012697:Serine Endopeptidases; C093329:TSV-PA protein, Trimeresurus stejnegeri; D013917:Thrombin; C032157:benzamidine