Title : Structure-based engineering of species selectivity in the interaction between urokinase and its
receptor : implication for preclinical cancer therapy
Abstract :
- The high affinity interaction between the urokinase-type plasminogen activator ( uPA ) and its glycolipid-anchored receptor ( uPAR ) is decisive for cell surface-associated plasminogen activation
- Because plasmin activity controls fibrinolysis in a variety of pathological conditions, including cancer and wound healing, several intervention studies have focused on targeting the uPA . uPAR interaction in vivo
- Evaluations of such studies in xenotransplanted tumor models are, however, complicated by the pronounced species selectivity in this interaction
- We now report the molecular basis underlying this difference by solving the crystal structure for the murine uPA . uPAR complex and demonstrate by extensive surface plasmon resonance studies that the kinetic rate constants for this interaction can be swapped completely between these orthologs by exchanging only two residues
- This study not only discloses the structural basis required for a successful rational design of the species selectivity in the uPA . uPAR interaction, which is highly relevant for functional studies in mouse models, but it also suggests the possible development of general inhibitors that will target the uPA . uPAR interaction across species barriers