|
|
| (6 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | + | |
| | ==Anthrax toxin lethal factor with bound small molecule inhibitor 16== | | ==Anthrax toxin lethal factor with bound small molecule inhibitor 16== |
| - | <StructureSection load='4pkv' size='340' side='right' caption='[[4pkv]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='4pkv' size='340' side='right'caption='[[4pkv]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4pkv]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PKV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PKV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4pkv]] 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=4PKV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PKV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=30R:N~2~-[4-(AMINOMETHYL)BENZYL]-N~2~-[(4-FLUORO-3-METHYLPHENYL)SULFONYL]-N-HYDROXY-D-ALANINAMIDE'>30R</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1jky|1jky]], [[1j7n|1j7n]], [[1pwp|1pwp]], [[1pwq|1pwq]], [[1pwu|1pwu]], [[1pwv|1pwv]], [[1pww|1pww]], [[1zxv|1zxv]], [[1yqy|1yqy]], [[4dv8|4dv8]], [[4pkq|4pkq]], [[4pkr|4pkr]], [[4pks|4pks]], [[4pkt|4pkt]], [[4pku|4pku]], [[4pkw|4pkw]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=30R:N~2~-[4-(AMINOMETHYL)BENZYL]-N~2~-[(4-FLUORO-3-METHYLPHENYL)SULFONYL]-N-HYDROXY-D-ALANINAMIDE'>30R</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4pkv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pkv OCA], [https://pdbe.org/4pkv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pkv RCSB], [https://www.ebi.ac.uk/pdbsum/4pkv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pkv ProSAT]</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=4pkv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pkv OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4pkv RCSB], [http://www.ebi.ac.uk/pdbsum/4pkv PDBsum]</span></td></tr> | + | |
| | </table> | | </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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 16: |
Line 18: |
| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4pkv" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Anthrax lethal factor 3D structures|Anthrax lethal factor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Hydrolase]] | + | [[Category: Bacillus anthracis]] |
| - | [[Category: Finzel, B C]] | + | [[Category: Large Structures]] |
| - | [[Category: Maize, K M]] | + | [[Category: Finzel BC]] |
| - | [[Category: Anthrax toxin]] | + | [[Category: Maize KM]] |
| - | [[Category: Lethal factor]]
| + | |
| - | [[Category: Ligand-induced conformational change]]
| + | |
| - | [[Category: Metalloprotease]]
| + | |
| - | [[Category: Metalloproteinase]]
| + | |
| - | [[Category: Structural dynamic]]
| + | |
| 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 secreted anthrax toxin consists of three components: the protective antigen (PA), edema factor (EF) and lethal factor (LF). LF, a zinc metalloproteinase, compromises the host immune system primarily by targeting mitogen-activated protein kinase kinases in macrophages. Peptide substrates and small-molecule inhibitors bind LF in the space between domains 3 and 4 of the hydrolase. Domain 3 is attached on a hinge to domain 2 via residues Ile300 and Pro385, and can move through an angular arc of greater than 35 degrees in response to the binding of different ligands. Here, multiple LF structures including five new complexes with co-crystallized inhibitors are compared and three frequently populated LF conformational states termed `bioactive', `open' and `tight' are identified. The bioactive position is observed with large substrate peptides and leaves all peptide-recognition subsites open and accessible. The tight state is seen in unliganded and small-molecule complex structures. In this state, domain 3 is clamped over certain substrate subsites, blocking access. The open position appears to be an intermediate state between these extremes and is observed owing to steric constraints imposed by specific bound ligands. The tight conformation may be the lowest-energy conformation among the reported structures, as it is the position observed with no bound ligand, while the open and bioactive conformations are likely to be ligand-induced.
Anthrax toxin lethal factor domain 3 is highly mobile and responsive to ligand binding.,Maize KM, Kurbanov EK, De La Mora-Rey T, Geders TW, Hwang DJ, Walters MA, Johnson RL, Amin EA, Finzel BC Acta Crystallogr D Biol Crystallogr. 2014 Nov;70(Pt 11):2813-22. doi:, 10.1107/S1399004714018161. Epub 2014 Oct 16. PMID:25372673[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
- ↑ Maize KM, Kurbanov EK, De La Mora-Rey T, Geders TW, Hwang DJ, Walters MA, Johnson RL, Amin EA, Finzel BC. Anthrax toxin lethal factor domain 3 is highly mobile and responsive to ligand binding. Acta Crystallogr D Biol Crystallogr. 2014 Nov;70(Pt 11):2813-22. doi:, 10.1107/S1399004714018161. Epub 2014 Oct 16. PMID:25372673 doi:http://dx.doi.org/10.1107/S1399004714018161
|
