Abstract
The major ligand binding site of platelet integrin alphaIIbbeta3, an essential receptor for hemostasis and thrombosis, lies between the head regions of its alpha and beta subunits. The Arginine-Glycine-Aspartic Acid (RGD) cell attachment sequence mediates the binding of several different adhesive plasma proteins to integrin alphaIIbbeta3. This sequence binds to both alphaIIb and beta3 residues in the ligand binding pocket, as well as to a divalent metal ion contained in the beta3 subunit. We recently identified a novel alphaIIbbeta3 antagonist (RUC-1) that binds exclusively to alphaIIb. In the present study we searched for additional new druggable binding sites of the integrin alphaIIbbeta3 headpiece along the conformational transition between its closed and open (swung-out) conformations. Specifically, we considered ten different alphaIIbbeta3 conformations resulting from a linear interpolation between the two extreme conformations of alphaIIbbeta3, and relaxed them by multi-nanosecond molecular dynamics simulations. Each trajectory was clustered by root mean square deviation over the protein Calpha atoms, and each cluster medoid was used as an input to a recent energy-based mapping algorithm (FTMAP) that searches an entire protein surface for consensus binding regions for a number of small organic probe molecules. Our results reveal new pockets at the beginning of the conformational transition whose structural information might be used as the basis for rational drug design of novel therapeutics targeting integrin alphaIIbbeta3.
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