4wf6

From Proteopedia

(Difference between revisions)

Revision as of 20:39, 30 November 2015

Anthrax toxin lethal factor with bound small molecule inhibitor MK-31

Structural highlights

4wf6 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4pkq, 4pkr, 4pks, 4pkt, 4pku, 4pkv, 4pkw, 1yqy, 5d1s, 5d1t, 5d1u
Activity:	Hydrolase, with EC number 3.4.24.83
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

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 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.

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
↑ Kurbanov EK, Chiu TL, Solberg J, Francis S, Maize KM, Fernandez J, Johnson RL, Hawkinson JE, Walters MA, Finzel BC, Amin EA. Probing the S2' Subsite of the Anthrax Toxin Lethal Factor Using Novel N-Alkylated Hydroxamates. J Med Chem. 2015 Nov 12;58(21):8723-33. doi: 10.1021/acs.jmedchem.5b01446. Epub, 2015 Oct 29. PMID:26492514 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01446

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4wf6"

@@ Line 4: / Line 4: @@
 <table><tr><td colspan='2'>[[4wf6]] is a 1 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WF6 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pkq|4pkq]], [[4pkr|4pkr]], [[4pks|4pks]], [[4pkt|4pkt]], [[4pku|4pku]], [[4pkv|4pkv]], [[4pkw|4pkw]], [[1yqy|1yqy]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pkq|4pkq]], [[4pkr|4pkr]], [[4pks|4pks]], [[4pkt|4pkt]], [[4pku|4pku]], [[4pkv|4pkv]], [[4pkw|4pkw]], [[1yqy|1yqy]], [[5d1s|5d1s]], [[5d1t|5d1t]], [[5d1u|5d1u]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Hydrolase Hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.24.83 3.4.24.83] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wf6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wf6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4wf6 RCSB], [http://www.ebi.ac.uk/pdbsum/4wf6 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wf6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wf6 OCA], [http://pdbe.org/4wf6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wf6 RCSB], [http://www.ebi.ac.uk/pdbsum/4wf6 PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 12: / Line 12: @@
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran- 4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.
+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.
-The discovery of a potent and selective lethal factor inhibitor for adjunct therapy of anthrax infection.,Xiong Y, Wiltsie J, Woods A, Guo J, Pivnichny JV, Tang W, Bansal A, Cummings RT, Cunningham BR, Friedlander AM, Douglas CM, Salowe SP, Zaller DM, Scolnick EM, Schmatz DM, Bartizal K, Hermes JD, MacCoss M, Chapman KT Bioorg Med Chem Lett. 2006 Feb 15;16(4):964-8. Epub 2005 Dec 9. PMID:16338135<ref>PMID:16338135</ref>
+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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4wf6" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>

4wf6

From Proteopedia

Revision as of 20:39, 30 November 2015

Anthrax toxin lethal factor with bound small molecule inhibitor MK-31

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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