Crystal Structure of the GpIbα-Thrombin Complex Essential for Platelet Aggregation

• DOI: 10.1126/science.1083917
• Publication Date: 2003-07-10T21:18:38Z
• Authors: John J. Dumas; Ravindra Kumar; Jasbir Seehra; William S. Somers; Lidia Mosyak
• Keywords: Blood Platelets; Models, Molecular; Binding Sites; Platelet Aggregation; Protein Conformation; Thrombin; Hydrogen Bonding; Crystallography, X-Ray; Protein Structure, Secondary; Protein Structure, Tertiary; Platelet Adhesiveness; Platelet Glycoprotein GPIb-IX Complex; Humans; Crystallization; Hydrophobic and Hydrophilic Interactions; Protein Binding

Direct interaction between platelet receptor glycoprotein Ibα (GpIbα) and thrombin is required for platelet aggregation and activation at sites of vascular injury. Abnormal GpIbα-thrombin binding is associated with many pathological conditions,including occlusive arterial thrombosis and bleeding disorders. The crystal structure of the GpIbα-thrombin complex at 2.6 angstrom resolution reveals simultaneous interactions of GpIbα with exosite I of one thrombin molecule,and with exosite II of a second thrombin molecule. In the crystal lattice,the periodic arrangement of GpIbα-thrombin complexes mirrors a scaffold that could serve as a driving force for tight platelet adhesion. The details of these interactions reconcile GpIbα-thrombin binding modes that are presently controversial,highlighting two distinct interfaces that are potential targets for development of novel antithrombotic drugs.