Topography of a 2.0 Å structure of α1-antitrypsin reveals targets for rational drug design to prevent conformational disease
Topography of a 2.0 Å structure of α1-antitrypsin reveals targets for rational drug design to prevent conformational disease
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DOI：
10.1110/ps.9.7.1274
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发表时间：
2000-07-01
期刊：
影响因子：
8
通讯作者：
Lomas, DA
中科院分区：
文献类型：
--
作者：
Elliott, PR;Pei, XY;Lomas, DA
丝氨酸蛋白酶抑制剂serpin家族的成员在炎症、凝血、纤溶和补体级联反应中发挥重要作用。它们功能的一个固有部分是经历结构重排的能力，即应力(S)到松弛(R)的转变，在这种转变中，一条额外的链被插入到中央的a- β片中。为了实现这种转换，A表必须具有不同寻常的灵活性。这种灵活性的故障可导致异常的蛋白质连接、蛇形蛋白失活和各种疾病，如肝硬化、血栓形成、血管性水肿、肺气肿和痴呆。控制这种构象重排的试剂的开发需要一个高分辨率的活性蛇形蛋白结构。我们在这里展示了原型serpin α(1)-抗胰蛋白酶的拓扑结构，分辨率为2埃。这种结构使我们能够确定五个空腔，这些空腔是合理药物设计的潜在目标，从而开发出能够防止构象转变和改善相关疾病的药物。
Members of the serpin family of serine proteinase inhibitors play important roles in the inflammatory, coagulation, fibrinolytic, and complement cascades. An inherent part of their function is the ability to undergo a structural rearrangement, the stressed (S) to relaxed (R) transition, in which an extra strand is inserted into the central A beta-sheet. In order for this transition to take place, the A sheet has to be unusually flexible. Malfunctions in this flexibility can lead to aberrant protein linkage, serpin inactivation, and diseases as diverse as cirrhosis, thrombosis, angioedema, emphysema, and dementia. The development of agents that control this conformational rearrangement requires a high resolution structure of an active serpin. We present here the topology of the archetypal serpin alpha(1)-antitrypsin to 2 Angstrom resolution. This structure allows us to define five cavities that are potential targets for rational drug design to develop agents that will prevent conformational transitions and ameliorate the associated disease.