The long term goal of this project is to understand the structural basis for the specificity of interactions among blood COAGULATION proteases, their inhibitors and their cofactors. Molecular details including water permable pockets and surface hydration will be computed analytically at atomic resolution using alpha shape based methods and available x-ray structures. Water transfer during functional interactions will be measured by osmotic stress technique using inert co-solutes excluded from water-permeable spaces and hydration layer of the proteins. Specifically, the aims of the proposal are: 1. Determination of the structural basis for the binding and activation of antithrombin by heparin and other glycosaminoglycans. 2. Analysis of protein-water interaction at the reactive loop and loop insertion regions of antithrombin during interaction with reactive loop peptides and glycosaminoglicans. 3. Characterization of hydration structure of tissue factor and tissue factor/factor VIIa complexes and its relationship to functional binding interaction. Analysis of structure/function relationship and water transfer during these interactions will evaluate the functional relevance of conformers in x-ray structures and will identify shape motifs of specific binding sites. This information will serve to develop therapies to prevent and control thromboembolic complications of cardiovascular disease.
| Levine, Howard A; McGee, Maria P; Serna, Susana (2010) Diffusion and reaction in the cell glycocalyx and the extracellular matrix. J Math Biol 60:1-26 |
| McGee, Maria; Wagner, William D (2003) Chondroitin sulfate anticoagulant activity is linked to water transfer: relevance to proteoglycan structure in atherosclerosis. Arterioscler Thromb Vasc Biol 23:1921-7 |
| McGee, Maria P; Liang, Jie; Luba, James (2002) Hydration effects of heparin on antithrombin probed by osmotic stress. Biophys J 82:1040-9 |
| McGee, M P; Liang, J (2001) Regulation of glycosaminoglycan function by osmotic potentials. Measurement of water transfer during antithrombin activation by heparin. J Biol Chem 276:49275-82 |
| McGee, M P; Chou, T (2001) Surface-dependent coagulation enzymes. Flow kinetics of factor Xa generation on live cell membranes. J Biol Chem 276:7827-35 |
