2gv6: Difference between revisions
New page: left|200px<br /> <applet load="2gv6" size="450" color="white" frame="true" align="right" spinBox="true" caption="2gv6, resolution 2.1Å" /> '''Crystal Structure of... |
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[[Image:2gv6.gif|left|200px]]<br /> | [[Image:2gv6.gif|left|200px]]<br /><applet load="2gv6" size="350" color="white" frame="true" align="right" spinBox="true" | ||
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caption="2gv6, resolution 2.1Å" /> | caption="2gv6, resolution 2.1Å" /> | ||
'''Crystal Structure of Matriptase with Inhibitor CJ-730'''<br /> | '''Crystal Structure of Matriptase with Inhibitor CJ-730'''<br /> | ||
==Overview== | ==Overview== | ||
Matriptase is an epithelium-derived type II transmembrane serine protease | 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== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
2GV6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with 730 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | 2GV6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=730:'>730</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2GV6 OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: matriptase]] | [[Category: matriptase]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:35:51 2008'' | ||
Revision as of 18:35, 21 February 2008
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Crystal Structure of Matriptase with Inhibitor CJ-730
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Ichthyosis with hypotrichosis OMIM:[606797]
About this StructureAbout this Structure
2GV6 is a Single protein structure of sequence from Homo sapiens with as ligand. Full crystallographic information is available from OCA.
ReferenceReference
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
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