3laq
Structure-based engineering of species selectivity in the uPA-uPAR interaction
Structural highlights
FunctionUROK_MOUSE Specifically cleaves the zymogen plasminogen to form the active enzyme plasmin. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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. Structure-based engineering of species selectivity in the interaction between urokinase and its receptor: implication for preclinical cancer therapy.,Lin L, Gardsvoll H, Huai Q, Huang M, Ploug M J Biol Chem. 2010 Apr 2;285(14):10982-92. Epub 2010 Feb 4. PMID:20133942[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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