This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
2nwn
From Proteopedia
(New page: 200px<br /><applet load="2nwn" size="350" color="white" frame="true" align="right" spinBox="true" caption="2nwn, resolution 2.15Å" /> '''New Pharmacophore fo...) |
|||
| Line 4: | Line 4: | ||
==Overview== | ==Overview== | ||
| - | Urokinase-type plasminogen activator (uPA) plays a crucial role in the | + | 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== | ==About this Structure== | ||
| Line 13: | Line 13: | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Andreasen, P | + | [[Category: Andreasen, P A.]] |
[[Category: Huang, M.]] | [[Category: Huang, M.]] | ||
[[Category: Huang, Z.]] | [[Category: Huang, Z.]] | ||
| - | [[Category: SGC, Structural | + | [[Category: SGC, Structural Genomics Consortium.]] |
[[Category: Wind, T.]] | [[Category: Wind, T.]] | ||
[[Category: Yuan, C.]] | [[Category: Yuan, C.]] | ||
| Line 29: | Line 29: | ||
[[Category: urokinase-type plasminogen activator]] | [[Category: urokinase-type plasminogen activator]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:11:51 2008'' |
Revision as of 16:11, 21 February 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 Thu Feb 21 18:11:51 2008
Categories: Homo sapiens | Protein complex | Andreasen, P A. | Huang, M. | Huang, Z. | SGC, Structural Genomics Consortium. | Wind, T. | Yuan, C. | Zhao, G. | Crystal structure | Hydrolase | Peptidyl inhibitor | Pharmacophore | Sgc | Structural genomics | Structural genomics consortium | Urokinase-type plasminogen activator
