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| | <StructureSection load='6ocw' size='340' side='right'caption='[[6ocw]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='6ocw' size='340' side='right'caption='[[6ocw]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6ocw]] is a 28 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OCW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OCW FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ocw]] is a 28 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OCW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OCW FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=M6M:N-{(2S)-1-({(2S)-1-[(2,4-difluorobenzyl)amino]-1-oxopropan-2-yl}amino)-4-[(2S)-2-methylpiperidin-1-yl]-1,4-dioxobutan-2-yl}-5-methyl-1,2-oxazole-3-carboxamide+(non-preferred+name)'>M6M</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]] 2.6Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">prcA, Rv2109c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU]), prcB, Rv2110c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DMF:DIMETHYLFORMAMIDE'>DMF</scene>, <scene name='pdbligand=M6M:N-{(2S)-1-({(2S)-1-[(2,4-difluorobenzyl)amino]-1-oxopropan-2-yl}amino)-4-[(2S)-2-methylpiperidin-1-yl]-1,4-dioxobutan-2-yl}-5-methyl-1,2-oxazole-3-carboxamide+(non-preferred+name)'>M6M</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Proteasome_endopeptidase_complex Proteasome endopeptidase complex], with EC number [http://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=6ocw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ocw OCA], [https://pdbe.org/6ocw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ocw RCSB], [https://www.ebi.ac.uk/pdbsum/6ocw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ocw 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=6ocw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ocw OCA], [http://pdbe.org/6ocw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ocw RCSB], [http://www.ebi.ac.uk/pdbsum/6ocw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ocw ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> [[http://www.uniprot.org/uniprot/PSB_MYCTU PSB_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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Myctu]] | + | [[Category: Mycobacterium tuberculosis H37Rv]] |
| - | [[Category: Proteasome endopeptidase complex]]
| + | [[Category: Hsu HC]] |
| - | [[Category: Hsu, H C]] | + | [[Category: Li H]] |
| - | [[Category: Li, H]] | + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Mycobacterium tuberculosis]]
| + | |
| - | [[Category: Phenylimidazole]]
| + | |
| - | [[Category: Proteasome inhibitor]]
| + | |
| 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]
Publication Abstract from PubMed
Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Co-evolving with its human host, Mycobacterium tuberculosis (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders non-replicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for anti-Mtb agents. Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, we developed phenylimidazole-based peptidomimetics that are highly potent for Mtb20S. X-ray structures of selected compounds with Mtb20S shed light on their selectivity for mycobacterial rather than human proteasomes.
Selective Phenylimidazole-based Inhibitors of the Mycobacterium tuberculosis Proteasome.,Zhan W, Hsu HC, Morgan T, Ouellette T, Burns-Huang K, Hara R, Wright AG, Imaeda T, Okamoto R, Sato K, Michino M, Ramjee M, Aso K, Meinke P, Foley M, Nathan CF, Li H, Lin G J Med Chem. 2019 Sep 27. doi: 10.1021/acs.jmedchem.9b01187. PMID:31560200[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
- ↑ Zhan W, Hsu HC, Morgan T, Ouellette T, Burns-Huang K, Hara R, Wright AG, Imaeda T, Okamoto R, Sato K, Michino M, Ramjee M, Aso K, Meinke P, Foley M, Nathan CF, Li H, Lin G. Selective Phenylimidazole-based Inhibitors of the Mycobacterium tuberculosis Proteasome. J Med Chem. 2019 Sep 27. doi: 10.1021/acs.jmedchem.9b01187. PMID:31560200 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01187
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