Celikel Reha, McClintock Richard A, Roberts James R, Mendolicchio G Loredana, Ware Jerry, Varughese Kottayil I, Ruggeri Zaverio M
Roon Research Center for Arteriosclerosis and Thrombosis, Division of Experimental Thrombosis and Hemostasis, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science. 2003 Jul 11;301(5630):218-21. doi: 10.1126/science.1084183.
Thrombin bound to platelets contributes to stop bleeding and, in pathological conditions, may cause vascular thrombosis. We have determined the structure of platelet glycoprotein Ibalpha (GpIbalpha) bound to thrombin at 2.3 angstrom resolution and defined two sites in GpIbalpha that bind to exosite II and exosite I of two distinct alpha-thrombin molecules, respectively. GpIbalpha 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 GpIbalpha clustering and cleavage of protease-activated receptors, which promote platelet activation, while limiting fibrinogen clotting through blockade of exosite I.
与血小板结合的凝血酶有助于止血，而在病理状态下，可能会导致血管血栓形成。我们已确定了与凝血酶结合的血小板糖蛋白Ibalpha（GpIbalpha）的结构，分辨率为2.3埃，并确定了GpIbalpha中分别与两个不同的α-凝血酶分子的外位点II和外位点I结合的两个位点。GpIbalpha的占据可能是顺序性的，因为与α-凝血酶外位点I结合的位点在未占据的受体中似乎是隐蔽的，但当第一个凝血酶分子通过外位点II结合时会暴露出来。这些相互作用可能通过介导GpIbalpha聚集和蛋白酶激活受体的裂解来调节α-凝血酶的功能，这会促进血小板激活，同时通过阻断外位点I来限制纤维蛋白原凝血。
