4wf6: Difference between revisions
New page: '''Unreleased structure''' The entry 4wf6 is ON HOLD Authors: Maize, K.M., Finzel, B.C., De la Mora-Rey, T. Description: Anthrax toxin lethal factor with bound small molecule inhibitor... |
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The | ==Anthrax toxin lethal factor with bound small molecule inhibitor MK-31== | ||
<StructureSection load='4wf6' size='340' side='right'caption='[[4wf6]], [[Resolution|resolution]] 2.65Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4wf6]] 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=4WF6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WF6 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]] 2.6521Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=407:N~2~-[(4-FLUORO-3-METHYLPHENYL)SULFONYL]-N-HYDROXY-D-ALANINAMIDE'>407</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=4wf6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wf6 OCA], [https://pdbe.org/4wf6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wf6 RCSB], [https://www.ebi.ac.uk/pdbsum/4wf6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wf6 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 lethal factor (LF) enzyme secreted by Bacillus anthracis is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies of the design of small molecule LF inhibitors have been conducted, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2' subsite has not yet been systematically explored as a potential target for lead optimization. Here we present synthesis, experimental evaluation, modeling, and structural biology for a novel series of sulfonamide hydroxamate LF inhibitor analogues specifically designed to extend into, and probe chemical preferences of, this S2' subsite. We discovered that this region accommodates a wide variety of chemical functionalities and that a broad selection of ligand structural modifications directed to this area can be incorporated without significant deleterious alterations in biological activity. We also identified key residues in this subsite that can potentially be targeted to improve inhibitor binding. | |||
Probing the S2' Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates.,Kurbanov EK, Chiu TL, Solberg J, Francis S, Maize KM, Fernandez J, Johnson RL, Hawkinson JE, Walters MA, Finzel BC, Amin EA J Med Chem. 2015 Nov 12;58(21):8723-33. doi: 10.1021/acs.jmedchem.5b01446. Epub, 2015 Oct 29. PMID:26492514<ref>PMID:26492514</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4wf6" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Anthrax lethal factor 3D structures|Anthrax lethal factor 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bacillus anthracis]] | |||
[[Category: Large Structures]] | |||
[[Category: De la Mora-Rey T]] | |||
[[Category: Finzel BC]] | |||
[[Category: Maize KM]] | |||
Latest revision as of 10:30, 27 September 2023
Anthrax toxin lethal factor with bound small molecule inhibitor MK-31Anthrax toxin lethal factor with bound small molecule inhibitor MK-31
Structural highlights
FunctionLEF_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 PubMedThe lethal factor (LF) enzyme secreted by Bacillus anthracis is a zinc hydrolase that is chiefly responsible for anthrax-related cell death. Although many studies of the design of small molecule LF inhibitors have been conducted, no LF inhibitor is yet available as a therapeutic agent. Inhibitors with considerable chemical diversity have been developed and investigated; however, the LF S2' subsite has not yet been systematically explored as a potential target for lead optimization. Here we present synthesis, experimental evaluation, modeling, and structural biology for a novel series of sulfonamide hydroxamate LF inhibitor analogues specifically designed to extend into, and probe chemical preferences of, this S2' subsite. We discovered that this region accommodates a wide variety of chemical functionalities and that a broad selection of ligand structural modifications directed to this area can be incorporated without significant deleterious alterations in biological activity. We also identified key residues in this subsite that can potentially be targeted to improve inhibitor binding. Probing the S2' Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates.,Kurbanov EK, Chiu TL, Solberg J, Francis S, Maize KM, Fernandez J, Johnson RL, Hawkinson JE, Walters MA, Finzel BC, Amin EA J Med Chem. 2015 Nov 12;58(21):8723-33. doi: 10.1021/acs.jmedchem.5b01446. Epub, 2015 Oct 29. PMID:26492514[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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