A MOLECULAR-MODEL OF THE SERINE-PROTEASE DOMAIN OF ACTIVATED PROTEIN-C - APPLICATION TO THE STUDY OF MISSENSE MUTATIONS CAUSING PROTEIN-C DEFICIENCY

A molecular model of the serine protease domain of protein C was const ructed by standard comparative methods. Individual missense mutations were inserted into the model and plausible explanations for their inte rference with protein C structure/function were derived through consid eration of location, steric effects and protein stability. A hydrophil ic cluster of many Arg and Lys residues, found adjacent to the active site cleft, is proposed to be involved in thrombomodulin and/or protei n S interactions. Analysis of comparative binding studies also suggest ed the presence of an extended substrate binding pocket in the model.