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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''' | '''New Pharmacophore for Serine Protease Inhibition Revealed by Crystal Structure of Human Urokinase-type Plasminogen Activator Complexed with a Cyclic Peptidyl Inhibitor, upain-1''' | ||
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[[Category: Yuan, C.]] | [[Category: Yuan, C.]] | ||
[[Category: Zhao, G.]] | [[Category: Zhao, G.]] | ||
[[Category: | [[Category: Crystal structure]] | ||
[[Category: | [[Category: Hydrolase]] | ||
[[Category: | [[Category: Peptidyl inhibitor]] | ||
[[Category: | [[Category: Pharmacophore]] | ||
[[Category: | [[Category: Sgc]] | ||
[[Category: | [[Category: Structural genomic]] | ||
[[Category: | [[Category: Structural genomics consortium]] | ||
[[Category: | [[Category: Urokinase-type plasminogen activator]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:00:12 2008'' | |||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | |||
Revision as of 07:00, 4 May 2008
New Pharmacophore for Serine Protease Inhibition Revealed by Crystal Structure of Human Urokinase-type Plasminogen Activator Complexed with a Cyclic Peptidyl Inhibitor, upain-1
Overview
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 2.15 A. 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 Structure
2NWN is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 Page seeded by OCA on Sun May 4 10:00:12 2008
