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Science 11 July 2003:
Vol. 301. no. 5630, pp. 222 - 226
DOI: 10.1126/science.1083917
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Reports

Crystal Structure of the GpIb{alpha}-Thrombin Complex Essential for Platelet Aggregation

John J. Dumas, Ravindra Kumar, Jasbir Seehra, William S. Somers,* Lidia Mosyak*

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

Department of Chemical and Screening Sciences, Wyeth, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.

* To whom correspondence should be addressed. E-mail: wsomers{at}wyeth.com (W.S.S.), lmosyak{at}wyeth.com (L.M.)

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