止血和血栓培训课件.ppt

* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * Top, schematic representation of prothrombin composed of fragment 1 (residues 1–155), fragment 2 (residues 156–271), and a protease domain (residues 272–579). Fragment-1 contains a Gla domain (residues 1–44) and a kringle (residues 65–143), fragment-2 contains a second kringle (residues 170–248), and the protease domain contains the A (residues 272–320) and B (residues 321–579) chains. Thrombin is generated by two cleavages at Arg-271 and Arg-320, producing the inactive precursor prethrombin-2 and the active intermediate meizothrombin, respectively. The A and B chain remain covalently attached after activation through the disulfide bond Cys-293–Cys-439 (Cys-1–Cys-122). Cleavage at Arg-284 by thrombin itself reduces the length of the A chain to its final 36 amino acids composition. Bottom, x-ray crystal structure of Gla-domainless prothrombin with kringle-1 (red) positioned at an angle of 36° relative to kringle 2 (green) that is coaxial to the protease domain (B chain in yellow and A chain in orange). The active site region is indicated by a circle, and the termini for each domain visible in the orientation are noted. Of the two sites of cleavage, Arg-320 (Arg-15) in the activation domain is visible, but Arg-271 is part of a 20-residue segment missing in the electron density map because of disorder. * SERPIN都具有相对保守的同源氨基酸序列以及相似的三维空间结构。天然的SERPIN都折叠成一种压稳态或者称作相对稳定的构象。它们都具有一个暴露在分子表面的黄色的反应环，具有一个活性中心P1氨基酸共它们的靶蛋白酶切割。同时它们也都具有一个红色的中心片层结构。大家如果仔细观看SERPIN的这个中心片层结构，会发现这5个片层从右往左的编号为12356，但没有第四，这是为什么呢？ * 这是因为SERPIN通过一种独特的机制来抑制他们的靶蛋白酶。一旦蛋白酶识别了SERPIN反应环上的活性位点P1基团，并对它进行切割，SERPIN就会很快发生急剧的构象变化，那个反应环会插入中心片成结构，变成第四条链。在这过程中蛋白酶会从SERPIN分子的顶端部甩到底部，然后由于分子间的相互挤压，导致这个共价键相联的蛋白酶失去活性。这样SERPIN也会从天然的具有5个片层的亚稳态转变成一种具有6个片层的超稳态。 * * * * * * * * * Top, schematic representation of prothrombin composed of fragment 1 (residues 1–155), fragment 2 (residues 1