Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide
André Ménez, M.H. Le Du, M. Ploug, B. Gilquin, E. Stura

The human urokinase-type plasminogen activator receptor (uPAR/CD87) is expressed at the invasive areas of the tumor-stromal microenvironment in many human cancers. We have solved the crystal structure of a soluble form of uPAR at 2.7 A° in association with a competitive peptide inhibitor of the urokinase plasminogen activator (uPA)–uPAR interaction. uPAR is composed of three consecutive domains organized in an almost circular manner. Each domain adopts a three-fingered fold that is also observed in snake toxins and in CD59. The three domains of uPAR generate both a deep internal cavity where the peptide binds in a helical conformation, and a large external surface. This knowledge combined with the discovery of a convergent binding motif shared by the antagonist peptide and uPA allowed us to build a model of the human uPA–uPAR complex. This model reveals that the receptor binding module of uPA engages the uPAR central cavity, thus leaving the external receptor surface accessible for other protein interactions (vitronectin and integrins). By this unique structural assembly, uPAR can orchestrate the fine interplay with the partners that are required to guide uPA-focalized proteolysis on the cell surface and control cell adhesion and migration.

Reference
Llinas et al., The EMBO Journal (2005) 24, 1655–1663