Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes

Abstract

The urokinase receptor (uPAR) can recognize several ligands. The structural basis for this multiple ligand recognition by uPAR is unknown. This study reports the crystal structures of uPAR in complex with both urokinase (uPA) and vitronectin and reveal that uPA occupies the central cavity of the receptor, whereas vitronectin binds at the outer side of the receptor. These results provide a structural understanding of one receptor binding to two ligands.

Figure 1

Recognition of both the uPA N-terminal fragment (ATF) and the vitronectin SMB domain by uPAR. Stereoview of superimposed crystal structures of the uPAR–ATF–SMB complex and the uPAR–ATF–SMB-antibody complex are shown (the antibody is omitted for clarity). The carbohydrate moieties of uPAR are shown in sticks. The three domains of uPAR are colored differently.

Figure 2

Details of the uPAR–SMB interface. (a) Interaction of the vitronectin SMB domain with uPAR D1 (orange) and D2 domains (magenta) in stereoview. Selected contacting residues in ball-and-stick representation; hydrogen bonds are shown in dashed lines. (b) Residues Phe13, Tyr28 and Asp22 of vitronectin (in ribbon and transparent surface representation) form an open pocket to bind Arg91 of uPAR (in ribbon and stick). Tyr27 and Tyr28 of the SMB domain insert into a large cavity of uPAR, showing shape complementarity of this interface.