2nwn

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(New page: 200px<br /><applet load="2nwn" size="350" color="white" frame="true" align="right" spinBox="true" caption="2nwn, resolution 2.15&Aring;" /> '''New Pharmacophore fo...)
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==Overview==
==Overview==
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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.
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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==
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Protein complex]]
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[[Category: Andreasen, P.A.]]
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[[Category: Andreasen, P A.]]
[[Category: Huang, M.]]
[[Category: Huang, M.]]
[[Category: Huang, Z.]]
[[Category: Huang, Z.]]
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[[Category: SGC, Structural.Genomics.Consortium.]]
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[[Category: SGC, Structural Genomics Consortium.]]
[[Category: Wind, T.]]
[[Category: Wind, T.]]
[[Category: Yuan, C.]]
[[Category: Yuan, C.]]
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[[Category: urokinase-type plasminogen activator]]
[[Category: urokinase-type plasminogen activator]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:52:59 2008''
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''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

Image:2nwn.gif

2nwn, resolution 2.15Å

Drag the structure with the mouse to rotate

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

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