6w9t: Difference between revisions

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 ==Crystal structure of Neisseria meningitidis ClpP protease complex with small molecule activator ACP1-06==
-<StructureSection load='6w9t' size='340' side='right'caption='[[6w9t]]' scene=''>
+<StructureSection load='6w9t' size='340' side='right'caption='[[6w9t]], [[Resolution|resolution]] 1.64&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W9T OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W9T FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6w9t]] is a 7 chain structure with sequence from [http://en.wikipedia.org/wiki/"diplokokkus_intracellularis_meningitidis"_(sic)_weichselbaum_1887 "diplokokkus intracellularis meningitidis" (sic) weichselbaum 1887]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6W9T OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6W9T FirstGlance]. <br>
-</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6w9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w9t OCA], [http://pdbe.org/6w9t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w9t RCSB], [http://www.ebi.ac.uk/pdbsum/6w9t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w9t ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=KHS:N-{2-[(2-chlorophenyl)sulfanyl]ethyl}-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]sulfonyl}propanamide'>KHS</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">clpP, COI09_01760, ERS514410_00057 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=487 "Diplokokkus intracellularis meningitidis" (sic) Weichselbaum 1887])</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'>[http://proteopedia.org/fgij/fg.htm?mol=6w9t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6w9t OCA], [http://pdbe.org/6w9t PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6w9t RCSB], [http://www.ebi.ac.uk/pdbsum/6w9t PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6w9t ProSAT]</span></td></tr>
 </table>
+== Function ==
+[[http://www.uniprot.org/uniprot/A0A0Y5K536_NEIME A0A0Y5K536_NEIME]] 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.[HAMAP-Rule:MF_00444][RuleBase:RU000550][SAAS:SAAS00674840]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Evolving antimicrobial resistance has motivated the search for novel targets and alternative therapies. Caseinolytic protease (ClpP) has emerged as an enticing new target since its function is conserved and essential for bacterial fitness, and because its inhibition or dysregulation leads to bacterial cell death. ClpP protease function controls global protein homeostasis and is, therefore, crucial for the maintenance of the bacterial proteome during growth and infection. Previously, acyldepsipeptides (ADEPs) were discovered to dysregulate ClpP, leading to bactericidal activity against both actively growing and dormant Gram-positive pathogens. Unfortunately, these compounds had very low efficacy against Gram-negative bacteria. Hence, we sought to develop non-ADEP ClpP-targeting compounds with activity against Gram-negative species and called these activators of self-compartmentalizing proteases (ACPs). These ACPs bind and dysregulate ClpP in a manner similar to ADEPs, effectively digesting bacteria from the inside out. Here, we performed further ACP derivatization and testing to improve the efficacy and breadth of coverage of selected ACPs against Gram-negative bacteria. We observed that a diverse collection of Neisseria meningitidis and Neisseria gonorrhoeae clinical isolates were exquisitely sensitive to these ACP analogues. Furthermore, based on the ACP-ClpP cocrystal structure solved here, we demonstrate that ACPs could be designed to be species specific. This validates the feasibility of drug-based targeting of ClpP in Gram-negative bacteria.
+Development of Antibiotics That Dysregulate the Neisserial ClpP Protease.,Binepal G, Mabanglo MF, Goodreid JD, Leung E, Barghash MM, Wong KS, Lin F, Cossette M, Bansagi J, Song B, Balasco Serrao VH, Pai EF, Batey RA, Gray-Owen SD, Houry WA ACS Infect Dis. 2020 Nov 25. doi: 10.1021/acsinfecdis.0c00599. PMID:33237740<ref>PMID:33237740</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6w9t" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Endopeptidase Clp]]
 [[Category: Large Structures]]
-[[Category: Houry WA]]
+[[Category: Houry, W A]]
-[[Category: Mabanglo MF]]
+[[Category: Mabanglo, M F]]
+[[Category: Activator]]
+[[Category: Antibacterial drug]]
+[[Category: Complex]]
+[[Category: Hydrolase]]
+[[Category: Proteostasis]]
+[[Category: Serine protease]]