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PMID: 15861141 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Crystal structure of the human urokinase plasminogen activator receptor bound to an antagonist peptide.

The EMBO journal ·Vol. 24 ·No. 9 ·2005-05-04 ·Pages 1655-63

Llinas P, Le Du MH, Gårdsvoll H, Danø K, Ploug M, Gilquin B, Stura EA, Ménez A

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.

MeSH Terms
Crystallization/methods Humans Molecular Conformation Peptides/chemistry,metabolism Protein Binding Receptors, Cell Surface/antagonists & inhibitors,chemistry,metabolism Receptors, Urokinase Plasminogen Activator Recombinant Proteins/chemistry Urokinase-Type Plasminogen Activator/chemistry,metabolism
Chemicals
PLAUR protein, human Peptides Receptors, Cell Surface Receptors, Urokinase Plasminogen Activator Recombinant Proteins Urokinase-Type Plasminogen Activator
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Llinas Paola
CEA, Département d'Ingénierie et d'Etudes des Protéines, CE Saclay, Gif sur Yvette, France.
Le Du Marie Hélène
Gårdsvoll Henrik
Danø Keld
Ploug Michael
Gilquin Bernard
Stura Enrico A
Ménez André
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1038/sj.emboj.7600635
Published
2005-05-04
Epub
2005-00-07
Pages
1655-63
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1142576
Subset
IM
Databases
PDB
1YWH
External Links
PubMed source DOI: 10.1038/sj.emboj.7600635 PMC Full Text View journal details
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