2nwn
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New Pharmacophore for Serine Protease Inhibition Revealed by Crystal Structure of Human Urokinase-type Plasminogen Activator Complexed with a Cyclic Peptidyl Inhibitor, upain-1
OverviewOverview
Urokinase-type plasminogen activator (uPA) plays a crucial role in the, regulation of plasminogen activation, tumor cell adhesion and migration., The inhibition of uPA activity is a promising mechanism for anti-cancer, therapy. A cyclic peptidyl inhibitor, upain-1, CSWRGLENHRMC, was, identified recently as a competitive and highly specific uPA inhibitor. We, determined the crystal structure of uPA in complex with upain-1 at 2.15A., The structure reveals that the cyclic peptide adopts a rigid conformation, stabilized by a disulfide bond (residues 1-12) and three tight beta turns, (residues 3-6, 6-9, 9-12). The Glu7 residue of upain-1 forms hydrogen, bonds with the main chain nitrogen atoms of residues 4, 5, and 6 of, upain-1, and is also critical for maintaining the active conformation of, upain-1. The Arg4 of upain-1 is inserted into the uPA's specific S1, pocket. The Ser2 residue of upain-1 locates close to the S1beta pocket of, uPA. The Gly5 and Glu7 residues of upain-1 occupy the S2 pocket and the, oxyanion hole of uPA, respectively. Furthermore, the Asn8 residue of, upain-1 binds to the 37- and 60-loops of uPA and renders the specificity, of upain-1 for uPA. Based on this structure, a new pharmacophore for the, design of highly specific uPA inhibitors was proposed.
About this StructureAbout this Structure
2NWN is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structural basis of specificity of a peptidyl urokinase inhibitor, upain-1., Zhao G, Yuan C, Wind T, Huang Z, Andreasen PA, Huang M, J Struct Biol. 2007 Oct;160(1):1-10. Epub 2007 Jun 20. PMID:17692534
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