3LAQ: Structure-Based Engineering Of Species Selectivity In The Upa-Upar Interaction

Citation:
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.
PDB ID: 3LAQDownload
MMDB ID: 79830
PDB Deposition Date: 2010/1/6
Updated in MMDB: 2012/10
Experimental Method:
x-ray diffraction
Resolution: 3.2  Å
Source Organism:
Similar Structures:
Biological Unit for 3LAQ: dimeric; determined by author and by software (PISA)
Molecular Components in 3LAQ
Label Count Molecule
Proteins (2 molecules)
1
Urokinase-type Plasminogen Activator(Gene symbol: Plau)
Molecule annotation
1
Urokinase Plasminogen Activator Surface Receptor(Gene symbol: Plaur)
Molecule annotation
Chemicals (4 molecules)
1
4
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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