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| - | [[Image:1pwp.gif|left|200px]]<br /><applet load="1pwp" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1pwp, resolution 2.90Å" /> | |
| - | '''Crystal Structure of the Anthrax Lethal Factor complexed with Small Molecule Inhibitor NSC 12155'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal Structure of the Anthrax Lethal Factor complexed with Small Molecule Inhibitor NSC 12155== |
| - | 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. | + | <StructureSection load='1pwp' size='340' side='right'caption='[[1pwp]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1pwp]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_anthracis Bacillus anthracis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PWP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PWP FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NSC:N,N-BIS(4-AMINO-2-METHYLQUINOLIN-6-YL)UREA'>NSC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1pwp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pwp OCA], [https://pdbe.org/1pwp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pwp RCSB], [https://www.ebi.ac.uk/pdbsum/1pwp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pwp ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/LEF_BACAN LEF_BACAN] One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. LF is the lethal factor that, when associated with PA, causes death. LF is not toxic by itself. It is a protease that cleaves the N-terminal of most dual specificity mitogen-activated protein kinase kinases (MAPKKs or MAP2Ks) (except for MAP2K5). Cleavage invariably occurs within the N-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes. There may be other cytosolic targets of LF involved in cytotoxicity. The proteasome may mediate a toxic process initiated by LF in the cell cytosol involving degradation of unidentified molecules that are essential for macrophage homeostasis. This is an early step in LeTx intoxication, but it is downstream of the cleavage by LF of MEK1 or other putative substrates.<ref>PMID:9563949</ref> <ref>PMID:9703991</ref> <ref>PMID:10475971</ref> <ref>PMID:11104681</ref> <ref>PMID:10338520</ref> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | 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==
| + | 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<ref>PMID:14718925</ref> |
| - | 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1PWP OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=14718925 14718925]
| + | </div> |
| - | [[Category: Anthrax lethal factor endopeptidase]]
| + | <div class="pdbe-citations 1pwp" style="background-color:#fffaf0;"></div> |
| - | [[Category: Bacillus anthracis]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Liddington, R.C.]]
| + | |
| - | [[Category: Schwarzenbacher, R.]]
| + | |
| - | [[Category: Wong, T.Y.]]
| + | |
| - | [[Category: NSC]]
| + | |
| - | [[Category: ZN]]
| + | |
| - | [[Category: anthrax toxin]]
| + | |
| - | [[Category: lethal factor]]
| + | |
| - | [[Category: small molecule inhibitor]]
| + | |
| | | | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 00:11:19 2007''
| + | ==See Also== |
| | + | *[[Anthrax lethal factor 3D structures|Anthrax lethal factor 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Bacillus anthracis]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Liddington RC]] |
| | + | [[Category: Schwarzenbacher R]] |
| | + | [[Category: Wong TY]] |
| Structural highlights
Function
LEF_BACAN One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. LF is the lethal factor that, when associated with PA, causes death. LF is not toxic by itself. It is a protease that cleaves the N-terminal of most dual specificity mitogen-activated protein kinase kinases (MAPKKs or MAP2Ks) (except for MAP2K5). Cleavage invariably occurs within the N-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes. There may be other cytosolic targets of LF involved in cytotoxicity. The proteasome may mediate a toxic process initiated by LF in the cell cytosol involving degradation of unidentified molecules that are essential for macrophage homeostasis. This is an early step in LeTx intoxication, but it is downstream of the cleavage by LF of MEK1 or other putative substrates.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
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.
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[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR, Copeland TD, Ahn NG, Oskarsson MK, Fukasawa K, Paull KD, Vande Woude GF. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science. 1998 May 1;280(5364):734-7. PMID:9563949
- ↑ Vitale G, Pellizzari R, Recchi C, Napolitani G, Mock M, Montecucco C. Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem Biophys Res Commun. 1998 Jul 30;248(3):706-11. PMID:9703991 doi:http://dx.doi.org/S0006-291X(98)99040-4
- ↑ Duesbery NS, Vande Woude GF. Anthrax lethal factor causes proteolytic inactivation of mitogen-activated protein kinase kinase. J Appl Microbiol. 1999 Aug;87(2):289-93. PMID:10475971
- ↑ Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C. Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J. 2000 Dec 15;352 Pt 3:739-45. PMID:11104681
- ↑ Tang G, Leppla SH. Proteasome activity is required for anthrax lethal toxin to kill macrophages. Infect Immun. 1999 Jun;67(6):3055-60. PMID:10338520
- ↑ 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. Identification of small molecule inhibitors of anthrax lethal factor. Nat Struct Mol Biol. 2004 Jan;11(1):67-72. Epub 2003 Dec 29. PMID:14718925 doi:10.1038/nsmb711
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