CRYSTAL STRUCTURE OF HUMAN UROKINASE PLASMINOGEN ACTIVATOR AMINO TERMINAL FRAGMENT BOUND TO ITS RECEPTOR

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 1.9ú by X-ray crystallography. Three consecutive domains of uPAR (Dl, D2 and D3) form the shape of a thick-walled teacup with a cone shape cavity in the middle, which has a wide opening (25ú) and large depth (14ú). 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 Dl 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.