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2. 发明申请

US20090264628A1 CRYSTAL STRUCTURE OF HUMAN UROKINASE PLASMINOGEN ACTIVATOR AMINO TEMINAL FRAGMENT BOUND TO ITS RECEPTOR 审中-公开
标题翻译：人类尿激酶等位基因激活剂的晶体结构氨基酸片段对其受体的影响
公开(公告)号：US20090264628A1
公开(公告)日：2009-10-22
申请号：US12089166
申请日：2006-10-03
申请人： Mingdong Huang , Qing Huai , Graham C. Parry , Douglas B. Cines , Andrew P. Mazar
发明人： Mingdong Huang , Qing Huai , Graham C. Parry , Douglas B. Cines , Andrew P. Mazar
IPC分类号： C07K16/00 , G06G7/48
CPC分类号： C07K16/40 , C07K14/705 , C07K2299/00 , C12N9/6462 , C12Y304/21073
摘要： Urokinase-type plasminogen activator (uPA) binds its cellular receptor (uPAR) with high affinity, thus localizing the generation of plasmin from plasminogen on the surface of a variety of cells. Disclosed herein is the structure of suPAR (uPAR1-277) complexed with the amino terminal fragment (ATF) of uPA (uPA1-143) at a resolution of 1.9 ú by X-ray crystallography. Three consecutive domains of uPAR (D1, D2 and D3) form the shape of a thick-walled teacup with a cone shape cavity in the middle, which has a wide opening (25 ú) and large depth (14 ú). uPA1-143 inserts into the cavity of uPAR and forms a large interface. The structure provides the basis for high affinity binding between uPA and uPAR and suggests the D1 and D2 domain of uPAR and the GFD domain of uPA (uPA7-43) are primarily responsible for uPA-uPAR binding. This structure presents the first high resolution view of uPA-uPAR interaction, and provides, among other things, a new platform for designing uPA-uPAR inhibitors/antagonists.
摘要翻译：尿激酶型纤溶酶原激活物（uPA）以高亲和力结合其细胞受体（uPAR），从而将多种细胞表面的纤溶酶原产生纤溶酶定位。本文公开了通过X射线晶体学以1.9μ的分辨率与uPA（uPA1-143）的氨基末端片段（ATF）复合的suPAR（uPAR1-277）的结构。 uPAR（D1，D2和D3）的三个连续的领域形成了一个厚壁茶杯的形状，中间有一个锥形腔，其宽敞的开口（25ú）和较大的深度（14ú）。 uPA1-143插入uPAR的腔体并形成大的界面。该结构为uPA和uPAR之间的高亲和力结合提供了基础，并提出uPAR的D1和D2结构域以及uPA（uPA7-43）的GFD结构域主要负责uPA-uPAR结合。该结构提供了uPA-uPAR相互作用的第一个高分辨率视图，并且提供了一个设计uPA-uPAR抑制剂/拮抗剂的新平台。

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