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Science 11 July 2003:
Vol. 301. no. 5630, pp. 218 - 221
DOI: 10.1126/science.1084183
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Reports

Modulation of {alpha}-Thrombin Function by Distinct Interactions with Platelet Glycoprotein Ib{alpha}

Reha Celikel,1 Richard A. McClintock,1 James R. Roberts,1 G. Loredana Mendolicchio,1 Jerry Ware,1 Kottayil I. Varughese,2* Zaverio M. Ruggeri1*

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 clotting through blockade of exosite I.

1 Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Thrombosis and Hemostasis; 2 Division of Cellular Biology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

* To whom correspondence should be addressed. E-mail: ruggeri{at}scripps.edu (Z.M.R.) and kiv{at}scripps.edu (K.I.V.)

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