1yqy
From Proteopedia
(New page: 200px<br /><applet load="1yqy" size="450" color="white" frame="true" align="right" spinBox="true" caption="1yqy, resolution 2.3Å" /> '''Structure of B. Anthr...) |
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| - | [[Image:1yqy.gif|left|200px]]<br /><applet load="1yqy" size=" | + | [[Image:1yqy.gif|left|200px]]<br /><applet load="1yqy" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1yqy, resolution 2.3Å" /> | caption="1yqy, resolution 2.3Å" /> | ||
'''Structure of B. Anthrax Lethal factor in complex with a hydroxamate inhibitor'''<br /> | '''Structure of B. Anthrax Lethal factor in complex with a hydroxamate inhibitor'''<br /> | ||
==Overview== | ==Overview== | ||
| - | The primary virulence factor of Bacillus anthracis is a secreted | + | The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolytic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H -pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (i) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ii) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (iii) approximately 50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of B. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (iv) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit "point of no return" model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax. |
==About this Structure== | ==About this Structure== | ||
| - | 1YQY 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 915 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:// | + | 1YQY 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=915:'>915</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=1YQY OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Felcetto, T.]] | [[Category: Felcetto, T.]] | ||
[[Category: Guo, J.]] | [[Category: Guo, J.]] | ||
| - | [[Category: Michael, B | + | [[Category: Michael, B F.]] |
| - | [[Category: Pivnichny, J | + | [[Category: Pivnichny, J V.]] |
| - | [[Category: Shoop, W | + | [[Category: Shoop, W L.]] |
[[Category: Wiltsie, J.]] | [[Category: Wiltsie, J.]] | ||
[[Category: Woods, A.]] | [[Category: Woods, A.]] | ||
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[[Category: toxin]] | [[Category: toxin]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:08:09 2008'' |
Revision as of 14:08, 21 February 2008
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Structure of B. Anthrax Lethal factor in complex with a hydroxamate inhibitor
Overview
The primary virulence factor of Bacillus anthracis is a secreted zinc-dependent metalloprotease toxin known as lethal factor (LF) that is lethal to the host through disruption of signaling pathways, cell destruction, and circulatory shock. Inhibition of this proteolytic-based LF toxemia could be expected to provide therapeutic value in combination with an antibiotic during and immediately after an active anthrax infection. Herein is shown the crystal structure of an intimate complex between a hydroxamate, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H -pyran-4-yl)acetamide, and LF at the LF-active site. Most importantly, this molecular interaction between the hydroxamate and the LF active site resulted in (i) inhibited LF protease activity in an enzyme assay and protected macrophages against recombinant LF and protective antigen in a cell-based assay, (ii) 100% protection in a lethal mouse toxemia model against recombinant LF and protective antigen, (iii) approximately 50% survival advantage to mice given a lethal challenge of B. anthracis Sterne vegetative cells and to rabbits given a lethal challenge of B. anthracis Ames spores and doubled the mean time to death in those that died in both species, and (iv) 100% protection against B. anthracis spore challenge when used in combination therapy with ciprofloxacin in a rabbit "point of no return" model for which ciprofloxacin alone provided 50% protection. These results indicate that a small molecule, hydroxamate LF inhibitor, as revealed herein, can ameliorate the toxemia characteristic of an active B. anthracis infection and could be a vital adjunct to our ability to combat anthrax.
About this Structure
1YQY 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
Anthrax lethal factor inhibition., Shoop WL, Xiong Y, Wiltsie J, Woods A, Guo J, Pivnichny JV, Felcetto T, Michael BF, Bansal A, Cummings RT, Cunningham BR, Friedlander AM, Douglas CM, Patel SB, Wisniewski D, Scapin G, Salowe SP, Zaller DM, Chapman KT, Scolnick EM, Schmatz DM, Bartizal K, MacCoss M, Hermes JD, Proc Natl Acad Sci U S A. 2005 May 31;102(22):7958-63. Epub 2005 May 23. PMID:15911756
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