Structure-based Engineering of Species Selectivity in the Interaction Between Urokinase and its Receptor: Implication for Preclinical Cancer Therapy

Journal Article · Fri Jan 01 00:00:00 EST 2010 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M109.093492· OSTI ID:1019679

Lin, L; Gardsvoll, H; Huai, Q; Huang, M; Ploug, M

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 {center_dot} 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 {center_dot} 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 {center_dot} 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 {center_dot} uPAR interaction across species barriers.

• Research Organization: Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
• Sponsoring Organization: DOE - OFFICE OF SCIENCE
• DOE Contract Number: DE-AC02-98CH10886
• OSTI ID: 1019679
• Report Number(s): BNL-95525-2011-JA; JBCHA3; TRN: US1103675
• Journal Information: Journal of Biological Chemistry, Vol. 285, Issue 14; ISSN 0021-9258
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
AFFINITY
CRYSTAL STRUCTURE
DESIGN
ENZYMES
FIBRINOLYSIN
FIBRINOLYSIS
FUNCTIONALS
HEALING
IN VIVO
KINETICS
MUTAGENESIS
NEOPLASMS
PLASMINOGEN
PLASMONS
PROTEIN STRUCTURE
RESIDUES
RESONANCE
TARGETS
THERAPY
UROKINASE
WOUNDS
national synchrotron light source