1d5j
From Proteopedia
(New page: 200px<br /> <applet load="1d5j" size="450" color="white" frame="true" align="right" spinBox="true" caption="1d5j, resolution 2.6Å" /> '''CRYSTAL STRUCTURE OF...) |
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| - | [[Image:1d5j.gif|left|200px]]<br /> | + | [[Image:1d5j.gif|left|200px]]<br /><applet load="1d5j" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1d5j" size=" | + | |
caption="1d5j, resolution 2.6Å" /> | caption="1d5j, resolution 2.6Å" /> | ||
'''CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.'''<br /> | '''CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The synthesis and enzyme inhibition data for a series of thiazine- and | + | The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1D5J is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with ZN, CA and MM3 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] Full crystallographic information is available from [http:// | + | 1D5J is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=CA:'>CA</scene> and <scene name='pdbligand=MM3:'>MM3</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Stromelysin_1 Stromelysin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.17 3.4.24.17] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D5J OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Stromelysin 1]] | [[Category: Stromelysin 1]] | ||
| - | [[Category: Almstead, N | + | [[Category: Almstead, N G.]] |
| - | [[Category: Bradley, R | + | [[Category: Bradley, R S.]] |
[[Category: De, B.]] | [[Category: De, B.]] | ||
| - | [[Category: Natchus, M | + | [[Category: Natchus, M G.]] |
[[Category: Pikul, S.]] | [[Category: Pikul, S.]] | ||
[[Category: CA]] | [[Category: CA]] | ||
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[[Category: zinc protease]] | [[Category: zinc protease]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:13:11 2008'' |
Revision as of 10:13, 21 February 2008
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CRYSTAL STRUCTURE OF MMP3 COMPLEXED WITH A THIAZEPINE BASED INHIBITOR.
Contents |
Overview
The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.
Disease
Known diseases associated with this structure: Coronary heart disease, susceptibility to OMIM:[185250]
About this Structure
1D5J is a Single protein structure of sequence from [1] with , and as ligands. Active as Stromelysin 1, with EC number 3.4.24.17 Full crystallographic information is available from OCA.
Reference
Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors., Almstead NG, Bradley RS, Pikul S, De B, Natchus MG, Taiwo YO, Gu F, Williams LE, Hynd BA, Janusz MJ, Dunaway CM, Mieling GE, J Med Chem. 1999 Nov 4;42(22):4547-62. PMID:10579818
Page seeded by OCA on Thu Feb 21 12:13:11 2008
Categories: Single protein | Stromelysin 1 | Almstead, N G. | Bradley, R S. | De, B. | Natchus, M G. | Pikul, S. | CA | MM3 | ZN | Inhibited | Mixed alpha beta structure | Zinc protease
