Modulation of [alpha]-thrombin function by distinct interactions with platelet glycoprotein Ib[alpha]

Thrombin bound to platelets contributes to stop bleeding and, in pathological conditions, may cause vascular thrombosis. We have determined the structure of platelet glycoprotein Ib[alpha] (GpIb[alpha]) bound to thrombin at 2.3 angstrom resolution and defined two sites in GpIb[alpha] that bind to exosite II and exosite I of two distinct [alpha]-thrombin molecules, respectively. GpIb[alpha] occupancy may be sequential as the site binding to [alpha]-thrombin exosite I appears to be cryptic in the unoccupied receptor but exposed when a first thrombin molecule is bound through exosite II. These interactions may modulate [alpha]-thrombin function by mediating GpIb[alpha] clustering and cleavage of protease-activated receptors, which promote platelet activation, while limiting fibrinogen dotting through blockade of exosite I.