title: Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide.
abstract: We report the crystal structure of a soluble form of human urokinase-type plasminogen activator receptor (uPAR/CD87), which is expressed at the invasive areas of the tumor-stromal microenvironment in many human cancers. The structure was solved at 2.7 A in association with a competitive peptide inhibitor of the urokinase-type plasminogen activator (uPA)-uPAR interaction. uPAR is composed of three consecutive three-finger domains organized in an almost circular manner, which generates 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.
authors.affiliation: CEA, Département d'Ingénierie et d'Etudes des Protéines, CE Saclay, Gif sur Yvette, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Llinas
authors.forename: Marie Hélène
authors.initials: MH
authors.lastname: Le Du
authors.forename: Henrik
authors.initials: H
authors.lastname: Gårdsvoll
authors.forename: Keld
authors.initials: K
authors.lastname: Danø
authors.forename: Michael
authors.initials: M
authors.lastname: Ploug
authors.forename: Bernard
authors.initials: B
authors.lastname: Gilquin
authors.forename: Enrico A
authors.initials: EA
authors.lastname: Stura
authors.forename: André
authors.initials: A
authors.lastname: Ménez
mesh_terms: D003460:Crystallization / Q000379:methods; D006801:Humans; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000737:chemistry; D014568:Urokinase-Type Plasminogen Activator / Q000737:chemistry / Q000378:metabolism
chemical_list: C524898:PLAUR protein, human; D010455:Peptides; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D014568:Urokinase-Type Plasminogen Activator