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4dv8

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==Anthrax Lethal Factor metalloproteinase in complex with the Hydroxamic acid based small molecule PT8421==
==Anthrax Lethal Factor metalloproteinase in complex with the Hydroxamic acid based small molecule PT8421==
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<StructureSection load='4dv8' size='340' side='right' caption='[[4dv8]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
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<StructureSection load='4dv8' size='340' side='right'caption='[[4dv8]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4dv8]] is a 1 chain structure with 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=4DV8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DV8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4dv8]] is a 1 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=4DV8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DV8 FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0LX:(2S)-6-[(4-FLUOROBENZYL)AMINO]-2-[(2R)-2-(4-FLUOROPHENYL)-2-METHOXYETHYL]-N-HYDROXYHEXANAMIDE'>0LX</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene><br>
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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]] 1.632&#8491;</td></tr>
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<tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">lef, pXO1-107, BXA0172, GBAA_pXO1_0172 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 Bacillus anthracis])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0LX:(2S)-6-[(4-FLUOROBENZYL)AMINO]-2-[(2R)-2-(4-FLUOROPHENYL)-2-METHOXYETHYL]-N-HYDROXYHEXANAMIDE'>0LX</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><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></td></tr>
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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=4dv8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dv8 OCA], [https://pdbe.org/4dv8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dv8 RCSB], [https://www.ebi.ac.uk/pdbsum/4dv8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dv8 ProSAT]</span></td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dv8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dv8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dv8 RCSB], [http://www.ebi.ac.uk/pdbsum/4dv8 PDBsum]</span></td></tr>
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</table>
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<table>
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== Function ==
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<div style="background-color:#fffaf0;">
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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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== Publication Abstract from PubMed ==
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Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication. Poor efficacy in the rat LT model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. Specific molecular interactions contributing to the high affinity of inhibitors with a secondary amine in the C2-side chain were revealed by X-ray crystallography.
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Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain.,Jiao GS, Kim S, Moayeri M, Crown D, Thai A, Cregar-Hernandez L, McKasson L, Sankaran B, Lehrer A, Wong T, Johns L, Margosiak SA, Leppla SH, Johnson AT Bioorg Med Chem Lett. 2012 Mar 15;22(6):2242-6. Epub 2012 Feb 1. PMID:22342144<ref>PMID:22342144</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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==See Also==
==See Also==
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*[[Anthrax Lethal Factor|Anthrax Lethal Factor]]
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*[[Anthrax lethal factor 3D structures|Anthrax lethal factor 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Anthrax lethal factor endopeptidase]]
 
[[Category: Bacillus anthracis]]
[[Category: Bacillus anthracis]]
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[[Category: Margosiak, S A.]]
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[[Category: Large Structures]]
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[[Category: Sankaran, B.]]
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[[Category: Margosiak SA]]
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[[Category: Endopeptidase]]
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[[Category: Sankaran B]]
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[[Category: Hydrolase]]
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[[Category: Zinc dependent]]
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Current revision

Anthrax Lethal Factor metalloproteinase in complex with the Hydroxamic acid based small molecule PT8421

PDB ID 4dv8

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