2gv6
From Proteopedia
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'''Crystal Structure of Matriptase with Inhibitor CJ-730''' | '''Crystal Structure of Matriptase with Inhibitor CJ-730''' | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Bode, W.]] | [[Category: Bode, W.]] | ||
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| - | [[Category: | + | [[Category: Inhibitor]] |
| - | [[Category: | + | [[Category: Matriptase]] |
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Revision as of 02:34, 4 May 2008
Crystal Structure of Matriptase with Inhibitor CJ-730
Contents |
Overview
Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with K(i) values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.
Disease
Known disease associated with this structure: Ichthyosis with hypotrichosis OMIM:[606797]
About this Structure
2GV6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase., Steinmetzer T, Schweinitz A, Sturzebecher A, Donnecke D, Uhland K, Schuster O, Steinmetzer P, Muller F, Friedrich R, Than ME, Bode W, Sturzebecher J, J Med Chem. 2006 Jul 13;49(14):4116-26. PMID:16821772 Page seeded by OCA on Sun May 4 05:34:37 2008
