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<StructureSection load='8b9u' size='340' side='right'caption='[[8b9u]], [[Resolution|resolution]] 2.25Å' scene=''> | <StructureSection load='8b9u' size='340' side='right'caption='[[8b9u]], [[Resolution|resolution]] 2.25Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8b9u]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[8b9u]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv] and [https://en.wikipedia.org/wiki/Nonomuraea_sp._MJM5123 Nonomuraea sp. MJM5123]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8B9U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8B9U 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]] 2.25Å</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]] 2.25Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E9M:N-methyl-L-tryptophan'>E9M</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=MAA:N-METHYL-L-ALANINE'>MAA</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene></td></tr> | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=E9M:N-methyl-L-tryptophan'>E9M</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=MAA:N-METHYL-L-ALANINE'>MAA</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</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=8b9u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b9u OCA], [https://pdbe.org/8b9u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b9u RCSB], [https://www.ebi.ac.uk/pdbsum/8b9u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b9u 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=8b9u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8b9u OCA], [https://pdbe.org/8b9u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8b9u RCSB], [https://www.ebi.ac.uk/pdbsum/8b9u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8b9u ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | |||
The ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria. To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism of the antibiotics cyclomarin A and ecumicin. Quantitative proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3. These proteins likely protect the Clp protease from excessive amounts of misfolded proteins or from cyclomarin A, which we show to mimic damaged proteins. To overcome the Clp security system, we developed a BacPROTAC that induces degradation of ClpC1 together with its ClpC2 caretaker. The dual Clp degrader, built from linked cyclomarin A heads, was highly efficient in killing pathogenic Mycobacterium tuberculosis, with >100-fold increased potency over the parent antibiotic. Together, our data reveal Clp scavenger proteins as important proteostasis safeguards and highlight the potential of BacPROTACs as future antibiotics. | |||
Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival.,Hoi DM, Junker S, Junk L, Schwechel K, Fischel K, Podlesainski D, Hawkins PME, van Geelen L, Kaschani F, Leodolter J, Morreale FE, Kleine S, Guha S, Rumpel K, Schmiedel VM, Weinstabl H, Meinhart A, Payne RJ, Kaiser M, Hartl M, Boehmelt G, Kazmaier U, Kalscheuer R, Clausen T Cell. 2023 May 11;186(10):2176-2192.e22. doi: 10.1016/j.cell.2023.04.009. Epub , 2023 May 2. PMID:37137307<ref>PMID:37137307</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8b9u" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: Nonomuraea sp. MJM5123]] | [[Category: Nonomuraea sp. MJM5123]] | ||
[[Category: Clausen T]] | [[Category: Clausen T]] | ||
[[Category: Hoi DM]] | [[Category: Hoi DM]] | ||
[[Category: Meinhart A]] | [[Category: Meinhart A]] | ||
Latest revision as of 12:28, 17 October 2024
Structure of ClpC1 NTD from Mycobacterium tuberculosisStructure of ClpC1 NTD from Mycobacterium tuberculosis
Structural highlights
Publication Abstract from PubMedThe ClpC1:ClpP1P2 protease is a core component of the proteostasis system in mycobacteria. To improve the efficacy of antitubercular agents targeting the Clp protease, we characterized the mechanism of the antibiotics cyclomarin A and ecumicin. Quantitative proteomics revealed that the antibiotics cause massive proteome imbalances, including upregulation of two unannotated yet conserved stress response factors, ClpC2 and ClpC3. These proteins likely protect the Clp protease from excessive amounts of misfolded proteins or from cyclomarin A, which we show to mimic damaged proteins. To overcome the Clp security system, we developed a BacPROTAC that induces degradation of ClpC1 together with its ClpC2 caretaker. The dual Clp degrader, built from linked cyclomarin A heads, was highly efficient in killing pathogenic Mycobacterium tuberculosis, with >100-fold increased potency over the parent antibiotic. Together, our data reveal Clp scavenger proteins as important proteostasis safeguards and highlight the potential of BacPROTACs as future antibiotics. Clp-targeting BacPROTACs impair mycobacterial proteostasis and survival.,Hoi DM, Junker S, Junk L, Schwechel K, Fischel K, Podlesainski D, Hawkins PME, van Geelen L, Kaschani F, Leodolter J, Morreale FE, Kleine S, Guha S, Rumpel K, Schmiedel VM, Weinstabl H, Meinhart A, Payne RJ, Kaiser M, Hartl M, Boehmelt G, Kazmaier U, Kalscheuer R, Clausen T Cell. 2023 May 11;186(10):2176-2192.e22. doi: 10.1016/j.cell.2023.04.009. Epub , 2023 May 2. PMID:37137307[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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