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| | <StructureSection load='5w18' size='340' side='right'caption='[[5w18]], [[Resolution|resolution]] 2.44Å' scene=''> | | <StructureSection load='5w18' size='340' side='right'caption='[[5w18]], [[Resolution|resolution]] 2.44Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5w18]] is a 28 chain structure with sequence from [http://en.wikipedia.org/wiki/Staa8 Staa8]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W18 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5W18 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5w18]] is a 28 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_NCTC_8325 Staphylococcus aureus subsp. aureus NCTC 8325] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W18 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W18 FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=9V7:'>9V7</scene>, <scene name='pdbligand=MP8:(4R)-4-METHYL-L-PROLINE'>MP8</scene>, <scene name='pdbligand=YCP:(2S)-PIPERIDINE-2-CARBOXYLIC+ACID'>YCP</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]] 2.44Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">clpP, SAOUHSC_00790 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=93061 STAA8])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9V7:phenylcarbamic+acid'>9V7</scene>, <scene name='pdbligand=MP8:(4R)-4-METHYL-L-PROLINE'>MP8</scene>, <scene name='pdbligand=YCP:(2S)-PIPERIDINE-2-CARBOXYLIC+ACID'>YCP</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Endopeptidase_Clp Endopeptidase Clp], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.92 3.4.21.92] </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=5w18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w18 OCA], [https://pdbe.org/5w18 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w18 RCSB], [https://www.ebi.ac.uk/pdbsum/5w18 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w18 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=5w18 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w18 OCA], [http://pdbe.org/5w18 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5w18 RCSB], [http://www.ebi.ac.uk/pdbsum/5w18 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5w18 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CLPP_STAA8 CLPP_STAA8]] Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity). | + | [https://www.uniprot.org/uniprot/CLPP_STAA8 CLPP_STAA8] Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Endopeptidase Clp]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Staa8]] | + | [[Category: Staphylococcus aureus subsp. aureus NCTC 8325]] |
| - | [[Category: Griffith, E C]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Lee, R E]] | + | [[Category: Griffith EC]] |
| - | [[Category: Clpp]] | + | [[Category: Lee RE]] |
| - | [[Category: Hydrolase-antibiotic complex]]
| + | |
| - | [[Category: Udep]]
| + | |
| Structural highlights
Function
CLPP_STAA8 Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity).
Publication Abstract from PubMed
Acyldepsipeptides are a unique class of antibiotics that act via allosterically dysregulated activation of the bacterial caseinolytic protease (ClpP). The ability of ClpP activators to kill nongrowing bacteria represents a new opportunity to combat deep-seated biofilm infections. However, the acyldepsipeptide scaffold is subject to rapid metabolism. Herein, we explore alteration of the potentially metabolically reactive alpha,beta unsaturated acyl chain. Through targeted synthesis, a new class of phenyl urea substituted depsipeptide ClpP activators with improved metabolic stability is described. The ureadepsipeptides are potent activators of Staphylococcus aureus ClpP and show activity against Gram-positive bacteria, including S. aureus biofilms. These studies demonstrate that a phenyl urea motif can successfully mimic the double bond, maintaining potency equivalent to acyldepsipeptides but with decreased metabolic liability. Although removal of the double bond from acyldepsipeptides generally has a significant negative impact on potency, structural studies revealed that the phenyl ureadepsipeptides can retain potency through the formation of a third hydrogen bond between the urea and the key Tyr63 residue in the ClpP activation domain. Ureadepsipeptides represent a new class of ClpP activators with improved drug-like properties, potent antibacterial activity, and the tractability to be further optimized.
Ureadepsipeptides as ClpP Activators.,Griffith EC, Zhao Y, Singh AP, Conlon BP, Tangallapally R, Shadrick WR, Liu J, Wallace MJ, Yang L, Elmore JM, Li Y, Zheng Z, Miller DJ, Cheramie MN, Lee RB, LaFleur MD, Lewis K, Lee RE ACS Infect Dis. 2019 Oct 24. doi: 10.1021/acsinfecdis.9b00245. PMID:31588734[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Griffith EC, Zhao Y, Singh AP, Conlon BP, Tangallapally R, Shadrick WR, Liu J, Wallace MJ, Yang L, Elmore JM, Li Y, Zheng Z, Miller DJ, Cheramie MN, Lee RB, LaFleur MD, Lewis K, Lee RE. Ureadepsipeptides as ClpP Activators. ACS Infect Dis. 2019 Oct 24. doi: 10.1021/acsinfecdis.9b00245. PMID:31588734 doi:http://dx.doi.org/10.1021/acsinfecdis.9b00245
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