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| | <StructureSection load='6cn8' size='340' side='right'caption='[[6cn8]], [[Resolution|resolution]] 1.40Å' scene=''> | | <StructureSection load='6cn8' size='340' side='right'caption='[[6cn8]], [[Resolution|resolution]] 1.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cn8]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884] and [http://en.wikipedia.org/wiki/Streptomyces_atratus Streptomyces atratus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CN8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CN8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cn8]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis] and [https://en.wikipedia.org/wiki/Streptomyces_atratus Streptomyces atratus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CN8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CN8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 1.4Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=F7P:'>F7P</scene>, <scene name='pdbligand=F7S:'>F7S</scene>, <scene name='pdbligand=F7V:'>F7V</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene>, <scene name='pdbligand=NIY:META-NITRO-TYROSINE'>NIY</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=F7P:1-[(3R)-3-hydroxy-2-methylbutan-2-yl]-L-tryptophan'>F7P</scene>, <scene name='pdbligand=F7S:(4S)-5-hydroxy-N-methyl-L-leucine'>F7S</scene>, <scene name='pdbligand=F7V:(2S,4E)-2-aminohex-4-enoic+acid'>F7V</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NIY:META-NITRO-TYROSINE'>NIY</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">clpC1, Rv3596c, MTCY07H7B.26 ([http://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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6cn8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cn8 OCA], [https://pdbe.org/6cn8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cn8 RCSB], [https://www.ebi.ac.uk/pdbsum/6cn8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cn8 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=6cn8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cn8 OCA], [http://pdbe.org/6cn8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cn8 RCSB], [http://www.ebi.ac.uk/pdbsum/6cn8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cn8 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CLPC1_MYCTU CLPC1_MYCTU]] ATP-dependent specificity component of the Clp protease. It directs the protease to specific substrates. Can perform chaperone functions in the absence of ClpP (By similarity). Degrades anti-sigma-E factor RseA in the presence of ClpP2. | + | [https://www.uniprot.org/uniprot/CLPC1_MYCTU CLPC1_MYCTU] ATP-dependent specificity component of the Clp protease. It directs the protease to specific substrates. Can perform chaperone functions in the absence of ClpP (By similarity). Degrades anti-sigma-E factor RseA in the presence of ClpP2. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6cn8" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6cn8" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Clp protease 3D structures|Clp protease 3D structures]] |
| | + | *[[Heat Shock Protein structures|Heat Shock Protein structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Streptomyces atratus]] | |
| - | [[Category: Abad-Zapatero, C]] | |
| - | [[Category: Wolf, N W]] | |
| - | [[Category: Atp-dependent protease]] | |
| - | [[Category: Atpase aaa+]] | |
| - | [[Category: Chaperone]] | |
| - | [[Category: Chaperone-antibiotic complex]] | |
| - | [[Category: Clpc1-ntd]] | |
| - | [[Category: Macrocyclic peptide]] | |
| | [[Category: Mycobacterium tuberculosis]] | | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Natural product]] | + | [[Category: Streptomyces atratus]] |
| - | [[Category: Rufomycin i]] | + | [[Category: Abad-Zapatero C]] |
| | + | [[Category: Wolf NW]] |
| Structural highlights
6cn8 is a 2 chain structure with sequence from Mycobacterium tuberculosis and Streptomyces atratus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 1.4Å |
| Ligands: | , , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
CLPC1_MYCTU ATP-dependent specificity component of the Clp protease. It directs the protease to specific substrates. Can perform chaperone functions in the absence of ClpP (By similarity). Degrades anti-sigma-E factor RseA in the presence of ClpP2.
Publication Abstract from PubMed
Addressing the urgent need to develop novel drugs against drug-resistant Mycobacterium tuberculosis ( M. tb) strains, ecumicin (ECU) and rufomycin I (RUFI) are being explored as promising new leads targeting cellular proteostasis via the caseinolytic protein ClpC1. Details of the binding topology and chemical mode of (inter)action of these cyclopeptides help drive further development of novel potency-optimized entities as tuberculosis drugs. ClpC1 M. tb protein constructs with mutations driving resistance to ECU and RUFI show reduced binding affinity by surface plasmon resonance (SPR). Despite certain structural similarities, ECU and RUFI resistant mutation sites did not overlap in their SPR binding patterns. SPR competition experiments show ECU prevents RUFI binding, whereas RUFI partially inhibits ECU binding. The X-ray structure of the ClpC1-NTD-RUFI complex reveals distinct differences compared to the previously reported ClpC1-NTD-cyclomarin A structure. Surprisingly, the complex structure revealed that the epoxide moiety of RUFI opened and covalently bound to ClpC1-NTD via the sulfur atom of Met1. Furthermore, RUFI analogues indicate that the epoxy group of RUFI is critical for binding and bactericidal activity. The outcomes demonstrate the significance of ClpC1 as a novel target and the importance of SAR analysis of identified macrocyclic peptides for drug discovery.
High-Resolution Structure of ClpC1-Rufomycin and Ligand Binding Studies Provide a Framework to Design and Optimize Anti-Tuberculosis Leads.,Wolf NM, Lee H, Choules MP, Pauli GF, Phansalkar R, Anderson JR, Gao W, Ren J, Santarsiero BD, Lee H, Cheng J, Jin YY, Ho NA, Duc NM, Suh JW, Abad-Zapatero C, Cho S ACS Infect Dis. 2019 May 3. doi: 10.1021/acsinfecdis.8b00276. PMID:30990022[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Wolf NM, Lee H, Choules MP, Pauli GF, Phansalkar R, Anderson JR, Gao W, Ren J, Santarsiero BD, Lee H, Cheng J, Jin YY, Ho NA, Duc NM, Suh JW, Abad-Zapatero C, Cho S. High-Resolution Structure of ClpC1-Rufomycin and Ligand Binding Studies Provide a Framework to Design and Optimize Anti-Tuberculosis Leads. ACS Infect Dis. 2019 May 3. doi: 10.1021/acsinfecdis.8b00276. PMID:30990022 doi:http://dx.doi.org/10.1021/acsinfecdis.8b00276
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