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| | <StructureSection load='3h6i' size='340' side='right'caption='[[3h6i]], [[Resolution|resolution]] 2.43Å' scene=''> | | <StructureSection load='3h6i' size='340' side='right'caption='[[3h6i]], [[Resolution|resolution]] 2.43Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3h6i]] is a 28 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H6I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H6I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3h6i]] is a 28 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3H6I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3H6I FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</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]] 2.43Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=OZT:(4S,5R)-5-METHYL-2-OXO-1,3-OXAZOLIDINE-4-CARBOXYLIC+ACID'>OZT</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=OZT:(4S,5R)-5-METHYL-2-OXO-1,3-OXAZOLIDINE-4-CARBOXYLIC+ACID'>OZT</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3h6f|3h6f]], [[2fhh|2fhh]], [[2fhg|2fhg]]</div></td></tr>
| + | |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">prcA, Rv2109c ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884]), MT2170, prcB, Rv2110c ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex Proteasome endopeptidase complex], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.25.1 3.4.25.1] </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=3h6i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h6i OCA], [https://pdbe.org/3h6i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h6i RCSB], [https://www.ebi.ac.uk/pdbsum/3h6i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h6i ProSAT]</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=3h6i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3h6i OCA], [https://pdbe.org/3h6i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3h6i RCSB], [https://www.ebi.ac.uk/pdbsum/3h6i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3h6i ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/PSA_MYCTO PSA_MYCTO]] Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation.[HAMAP-Rule:MF_00289] [[https://www.uniprot.org/uniprot/PSB_MYCTO PSB_MYCTO]] Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation.
| + | [https://www.uniprot.org/uniprot/PSA_MYCTU PSA_MYCTU] Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. The M.tuberculosis proteasome is able to cleave oligopeptides not only after hydrophobic but also after basic, acidic and small neutral residues. Among the identified substrates of the M.tuberculosis proteasome are the pupylated FabD, PanB and Mpa proteins. One function of the proteasome is to contribute to M.tuberculosis ability to resist killing by host macrophages, since the core proteasome is essential for persistence of the pathogen during the chronic phase of infection in mice. The mechanism of protection against bactericidal chemistries of the host's immune response probably involves the degradation of proteins that are irreversibly oxidized, nitrated, or nitrosated.<ref>PMID:16468985</ref> <ref>PMID:18059281</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Proteasome endopeptidase complex]] | |
| - | [[Category: Li, D]] | |
| - | [[Category: Li, H]] | |
| - | [[Category: Lin, G]] | |
| - | [[Category: Binding site]] | |
| - | [[Category: Hydrolase]] | |
| | [[Category: Mycobacterium tuberculosis]] | | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Oxazolidin-2-one]] | + | [[Category: Li D]] |
| - | [[Category: Protease inhibitor]] | + | [[Category: Li H]] |
| - | [[Category: Proteasome]] | + | [[Category: Lin G]] |
| - | [[Category: Protein subunit]]
| + | |
| - | [[Category: Substrate specificity]]
| + | |
| Structural highlights
Function
PSA_MYCTU Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. The M.tuberculosis proteasome is able to cleave oligopeptides not only after hydrophobic but also after basic, acidic and small neutral residues. Among the identified substrates of the M.tuberculosis proteasome are the pupylated FabD, PanB and Mpa proteins. One function of the proteasome is to contribute to M.tuberculosis ability to resist killing by host macrophages, since the core proteasome is essential for persistence of the pathogen during the chronic phase of infection in mice. The mechanism of protection against bactericidal chemistries of the host's immune response probably involves the degradation of proteins that are irreversibly oxidized, nitrated, or nitrosated.[1] [2]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis. Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-one compounds kill non-replicating M. tuberculosis and act as selective suicide-substrate inhibitors of the M. tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue.
Inhibitors selective for mycobacterial versus human proteasomes.,Lin G, Li D, de Carvalho LP, Deng H, Tao H, Vogt G, Wu K, Schneider J, Chidawanyika T, Warren JD, Li H, Nathan C Nature. 2009 Oct 1;461(7264):621-6. Epub 2009 Sep 16. PMID:19759536[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lin G, Hu G, Tsu C, Kunes YZ, Li H, Dick L, Parsons T, Li P, Chen Z, Zwickl P, Weich N, Nathan C. Mycobacterium tuberculosis prcBA genes encode a gated proteasome with broad oligopeptide specificity. Mol Microbiol. 2006 Mar;59(5):1405-16. PMID:16468985 doi:http://dx.doi.org/10.1111/j.1365-2958.2005.05035.x
- ↑ Gandotra S, Schnappinger D, Monteleone M, Hillen W, Ehrt S. In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice. Nat Med. 2007 Dec;13(12):1515-20. Epub 2007 Dec 2. PMID:18059281 doi:http://dx.doi.org/10.1038/nm1683
- ↑ Lin G, Li D, de Carvalho LP, Deng H, Tao H, Vogt G, Wu K, Schneider J, Chidawanyika T, Warren JD, Li H, Nathan C. Inhibitors selective for mycobacterial versus human proteasomes. Nature. 2009 Oct 1;461(7264):621-6. Epub 2009 Sep 16. PMID:19759536 doi:10.1038/nature08357
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