1pwq

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[[Image:1pwq.jpg|left|200px]]
 
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{{Structure
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==Crystal structure of Anthrax Lethal Factor complexed with Thioacetyl-Tyr-Pro-Met-Amide, a metal-chelating peptidyl small molecule inhibitor==
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|PDB= 1pwq |SIZE=350|CAPTION= <scene name='initialview01'>1pwq</scene>, resolution 3.52&Aring;
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<StructureSection load='1pwq' size='340' side='right'caption='[[1pwq]], [[Resolution|resolution]] 3.52&Aring;' scene=''>
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|SITE=
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== Structural highlights ==
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|LIGAND= <scene name='pdbligand=SD2:N-(SULFANYLACETYL)TYROSYLPROLYLMETHIONINAMIDE'>SD2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>
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<table><tr><td colspan='2'>[[1pwq]] 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=1PWQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1PWQ FirstGlance]. <br>
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|ACTIVITY= <span class='plainlinks'>[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] </span>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.52&#8491;</td></tr>
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|GENE= LEF ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 Bacillus anthracis])
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SD2:N-(SULFANYLACETYL)TYROSYLPROLYLMETHIONINAMIDE'>SD2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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|DOMAIN=
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1pwq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pwq OCA], [https://pdbe.org/1pwq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1pwq RCSB], [https://www.ebi.ac.uk/pdbsum/1pwq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1pwq ProSAT]</span></td></tr>
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|RELATEDENTRY=[[1pwp|1PWP]]
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</table>
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1pwq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1pwq OCA], [http://www.ebi.ac.uk/pdbsum/1pwq PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1pwq RCSB]</span>
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== Function ==
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}}
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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Recent events have created an urgent need for new therapeutic strategies to treat anthrax. We have applied a mixture-based peptide library approach to rapidly determine the optimal peptide substrate for the anthrax lethal factor (LF), a metalloproteinase with an important role in the pathogenesis of the disease. Using this approach we have identified peptide analogs that inhibit the enzyme in vitro and that protect cultured macrophages from LF-mediated cytolysis. The crystal structures of LF bound to an optimized peptide substrate and to peptide-based inhibitors provide a rationale for the observed selectivity and may be exploited in the design of future generations of LF inhibitors.
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'''Crystal structure of Anthrax Lethal Factor complexed with Thioacetyl-Tyr-Pro-Met-Amide, a metal-chelating peptidyl small molecule inhibitor'''
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The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor.,Turk BE, Wong TY, Schwarzenbacher R, Jarrell ET, Leppla SH, Collier RJ, Liddington RC, Cantley LC Nat Struct Mol Biol. 2004 Jan;11(1):60-6. Epub 2003 Dec 29. PMID:14718924<ref>PMID:14718924</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 1pwq" style="background-color:#fffaf0;"></div>
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==Overview==
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==See Also==
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Recent events have created an urgent need for new therapeutic strategies to treat anthrax. We have applied a mixture-based peptide library approach to rapidly determine the optimal peptide substrate for the anthrax lethal factor (LF), a metalloproteinase with an important role in the pathogenesis of the disease. Using this approach we have identified peptide analogs that inhibit the enzyme in vitro and that protect cultured macrophages from LF-mediated cytolysis. The crystal structures of LF bound to an optimized peptide substrate and to peptide-based inhibitors provide a rationale for the observed selectivity and may be exploited in the design of future generations of LF inhibitors.
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*[[Anthrax lethal factor 3D structures|Anthrax lethal factor 3D structures]]
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== References ==
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==About this Structure==
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<references/>
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1PWQ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Bacillus_anthracis Bacillus anthracis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PWQ OCA].
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__TOC__
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</StructureSection>
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==Reference==
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The structural basis for substrate and inhibitor selectivity of the anthrax lethal factor., Turk BE, Wong TY, Schwarzenbacher R, Jarrell ET, Leppla SH, Collier RJ, Liddington RC, Cantley LC, Nat Struct Mol Biol. 2004 Jan;11(1):60-6. Epub 2003 Dec 29. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14718924 14718924]
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[[Category: Anthrax lethal factor endopeptidase]]
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[[Category: Bacillus anthracis]]
[[Category: Bacillus anthracis]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Liddington, R C.]]
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[[Category: Liddington RC]]
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[[Category: Schwarzenbacher, R.]]
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[[Category: Schwarzenbacher R]]
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[[Category: Wong, T Y.]]
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[[Category: Wong TY]]
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[[Category: anthrax toxin]]
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[[Category: lethal factor]]
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[[Category: metal-chelator]]
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[[Category: small molecule peptidic inhibitor]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 23:05:35 2008''
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Current revision

Crystal structure of Anthrax Lethal Factor complexed with Thioacetyl-Tyr-Pro-Met-Amide, a metal-chelating peptidyl small molecule inhibitor

PDB ID 1pwq

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