Crystal structure of the von Willebrand factor modulator botrocetin

The binding of von Willebrand factor (vWF) to the platelet receptor, glycop rotein (GP) Ib-IX-V complex, has a key role in the initiation of thrombus f ormation and is regulated by interactions with extracellular matrix compone nts under the influence of hemodynamic forces. To a certain extent, these e ffects can be mimicked in vitro by two nonphysiologic modulators, ristoceti n and botrocetin. The latter, isolated from the venom of the snake Bothrops jararaca, is a 31-kDa heterodimeric protein that forms a soluble complex w ith VWF. As an initial step toward understanding the mechanisms that regula te VWF function, we have solved the crystal structure of botrocetin at 1.8 Angstrom resolution. Botrocetin exhibits homology with other snake proteins , but contains only one metal binding site as compared to two in Factor IX binding protein and Factor IX/X binding protein and none in flavocetin. A d istinctive feature of botrocetin is the presence of a negatively charged su rface that may play a role in the association with the vWF A1 domain.