2NWN

New Pharmacophore for Serine Protease Inhibition Revealed by Crystal Structure of Human Urokinase-type Plasminogen Activator Complexed with a Cyclic Peptidyl Inhibitor, upain-1

Summary for 2NWN

• Entry DOI: 10.2210/pdb2nwn/pdb
• Descriptor: Plasminogen activator, urokinase, upain-1 (3 entities in total)
• Functional Keywords: urokinase-type plasminogen activator, peptidyl inhibitor, pharmacophore, structural genomics, structural genomics consortium, sgc, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 29937.12

Authors

Zhao, G.,Yuan, C.,Wind, T.,Andreasen, P.A.,Huang, Z.,Huang, M.,Structural Genomics Consortium (SGC) (deposition date: 2006-11-16, release date: 2007-10-16, Last modification date: 2024-11-20)

Primary citation

Zhao, G.,Yuan, C.,Wind, T.,Huang, Z.,Andreasen, P.A.,Huang, M.
Structural basis of specificity of a peptidyl urokinase inhibitor, upain-1
J.Struct.Biol., 160:1-10, 2007

PubMed Abstract: 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.

PubMed: 17692534
DOI: 10.1016/j.jsb.2007.06.003

Experimental method

X-RAY DIFFRACTION (2.15 Å)