title: Crystal structure of the GpIbalpha-thrombin complex essential for platelet aggregation.
abstract: Direct interaction between platelet receptor glycoprotein Ibalpha (GpIbalpha) and thrombin is required for platelet aggregation and activation at sites of vascular injury. Abnormal GpIbalpha-thrombin binding is associated with many pathological conditions,including occlusive arterial thrombosis and bleeding disorders. The crystal structure of the GpIbalpha-thrombin complex at 2.6 angstrom resolution reveals simultaneous interactions of GpIbalpha with exosite I of one thrombin molecule,and with exosite II of a second thrombin molecule. In the crystal lattice,the periodic arrangement of GpIbalpha-thrombin complexes mirrors a scaffold that could serve as a driving force for tight platelet adhesion. The details of these interactions reconcile GpIbalpha-thrombin binding modes that are presently controversial,highlighting two distinct interfaces that are potential targets for development of novel antithrombotic drugs.
authors.affiliation: Department of Chemical and Screening Sciences, Wyeth, 200 Cambridge Park Drive, Cambridge, MA 02140, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Dumas
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kumar
authors.forename: Jasbir
authors.initials: J
authors.lastname: Seehra
authors.forename: William S
authors.initials: WS
authors.lastname: Somers
authors.forename: Lidia
authors.initials: L
authors.lastname: Mosyak
mesh_terms: D001665:Binding Sites; D001792:Blood Platelets / Q000737:chemistry / Q000502:physiology; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D010973:Platelet Adhesiveness; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; D013917:Thrombin