1pwp
From Proteopedia
(New page: 200px<br /><applet load="1pwp" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pwp, resolution 2.90Å" /> '''Crystal Structure of...) |
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| - | [[Image:1pwp.gif|left|200px]]<br /><applet load="1pwp" size=" | + | [[Image:1pwp.gif|left|200px]]<br /><applet load="1pwp" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1pwp, resolution 2.90Å" /> | caption="1pwp, resolution 2.90Å" /> | ||
'''Crystal Structure of the Anthrax Lethal Factor complexed with Small Molecule Inhibitor NSC 12155'''<br /> | '''Crystal Structure of the Anthrax Lethal Factor complexed with Small Molecule Inhibitor NSC 12155'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The virulent spore-forming bacterium Bacillus anthracis secretes anthrax | + | The virulent spore-forming bacterium Bacillus anthracis secretes anthrax toxin composed of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease that inactivates key signaling molecules, such as mitogen-activated protein kinase kinases (MAPKK), to ultimately cause cell death. We report here the identification of small molecule (nonpeptidic) inhibitors of LF. Using a two-stage screening assay, we determined the LF inhibitory properties of 19 compounds. Here, we describe six inhibitors on the basis of a pharmacophoric relationship determined using X-ray crystallographic data, molecular docking studies and three-dimensional (3D) database mining from the US National Cancer Institute (NCI) chemical repository. Three of these compounds have K(i) values in the 0.5-5 microM range and show competitive inhibition. These molecular scaffolds may be used to develop therapeutically viable inhibitors of LF. |
==About this Structure== | ==About this Structure== | ||
| - | 1PWP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacillus_anthracis Bacillus anthracis] with ZN and NSC as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Anthrax_lethal_factor_endopeptidase Anthrax lethal factor endopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.83 3.4.24.83] Full crystallographic information is available from [http:// | + | 1PWP is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bacillus_anthracis Bacillus anthracis] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=NSC:'>NSC</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Anthrax_lethal_factor_endopeptidase Anthrax lethal factor endopeptidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.83 3.4.24.83] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PWP OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Bacillus anthracis]] | [[Category: Bacillus anthracis]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Liddington, R | + | [[Category: Liddington, R C.]] |
[[Category: Schwarzenbacher, R.]] | [[Category: Schwarzenbacher, R.]] | ||
| - | [[Category: Wong, T | + | [[Category: Wong, T Y.]] |
[[Category: NSC]] | [[Category: NSC]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
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[[Category: small molecule inhibitor]] | [[Category: small molecule inhibitor]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:33:18 2008'' |
Revision as of 12:33, 21 February 2008
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Crystal Structure of the Anthrax Lethal Factor complexed with Small Molecule Inhibitor NSC 12155
Overview
The virulent spore-forming bacterium Bacillus anthracis secretes anthrax toxin composed of protective antigen (PA), lethal factor (LF) and edema factor (EF). LF is a Zn-dependent metalloprotease that inactivates key signaling molecules, such as mitogen-activated protein kinase kinases (MAPKK), to ultimately cause cell death. We report here the identification of small molecule (nonpeptidic) inhibitors of LF. Using a two-stage screening assay, we determined the LF inhibitory properties of 19 compounds. Here, we describe six inhibitors on the basis of a pharmacophoric relationship determined using X-ray crystallographic data, molecular docking studies and three-dimensional (3D) database mining from the US National Cancer Institute (NCI) chemical repository. Three of these compounds have K(i) values in the 0.5-5 microM range and show competitive inhibition. These molecular scaffolds may be used to develop therapeutically viable inhibitors of LF.
About this Structure
1PWP is a Single protein structure of sequence from Bacillus anthracis with and as ligands. Active as Anthrax lethal factor endopeptidase, with EC number 3.4.24.83 Full crystallographic information is available from OCA.
Reference
Identification of small molecule inhibitors of anthrax lethal factor., Panchal RG, Hermone AR, Nguyen TL, Wong TY, Schwarzenbacher R, Schmidt J, Lane D, McGrath C, Turk BE, Burnett J, Aman MJ, Little S, Sausville EA, Zaharevitz DW, Cantley LC, Liddington RC, Gussio R, Bavari S, Nat Struct Mol Biol. 2004 Jan;11(1):67-72. Epub 2003 Dec 29. PMID:14718925
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