View source for 8r05


==Photorhabdus lamondii ClpP in complex with the natural product beta-lactone inhibitor Cystargolide A at 2.5 A resolution==
<StructureSection load='8r05' size='340' side='right'caption='[[8r05]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8r05]] is a 14 chain structure with sequence from [https://en.wikipedia.org/wiki/Photorhabdus_laumondii Photorhabdus laumondii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8R05 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8R05 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=VSZ:(2~{S},3~{S})-2-[[(2~{S})-2-[[(2~{R},3~{S})-3-methanoyl-4-methyl-2-oxidanyl-pentanoyl]amino]-3-methyl-butanoyl]amino]-3-methyl-pentanoic+acid'>VSZ</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=8r05 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8r05 OCA], [https://pdbe.org/8r05 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8r05 RCSB], [https://www.ebi.ac.uk/pdbsum/8r05 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8r05 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CLPP_PHOLL CLPP_PHOLL] 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]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The caseinolytic protease is a highly conserved serine protease, crucial to prokaryotic and eukaryotic protein homeostasis, and a promising antibacterial and anticancer drug target. Herein, we describe the potent cystargolides as the first natural beta-lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic gene cluster in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target. We show the inhibition of Staphylococcus aureus ClpP by cystargolide A and B by different biochemical methods in vitro. Synthesis of semisynthetic derivatives and probes with improved cell penetration allowed us to confirm ClpP as a specific target in S. aureus cells and to demonstrate the anti-virulence activity of this natural product class. Crystal structures show cystargolide A covalently bound to all 14 active sites of ClpP from S. aureus, Aquifex aeolicus, and Photorhabdus laumondii, and reveal the molecular mechanism of ClpP inhibition by beta-lactones, the predominant class of ClpP inhibitors.

Structure of Staphylococcus aureus ClpP Bound to the Covalent Active-Site Inhibitor Cystargolide A.,Illigmann A, Vielberg MT, Lakemeyer M, Wolf F, Dema T, Stange P, Kuttenlochner W, Liebhart E, Kulik A, Staudt ND, Malik I, Grond S, Sieber SA, Kaysser L, Groll M, Brotz-Oesterhelt H Angew Chem Int Ed Engl. 2024 Jan 15;63(3):e202314028. doi: , 10.1002/anie.202314028. Epub 2023 Dec 12. PMID:38029352<ref>PMID:38029352</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8r05" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Photorhabdus laumondii]]
[[Category: Broetz-Oesterhelt H]]
[[Category: Dema T]]
[[Category: Groll M]]
[[Category: Grond S]]
[[Category: Illigmann A]]
[[Category: Kaysser L]]
[[Category: Kulik A]]
[[Category: Kuttenlochner W]]
[[Category: Lakemeyer M]]
[[Category: Liebhart E]]
[[Category: Malik I]]
[[Category: Sieber SA]]
[[Category: Stange P]]
[[Category: Staudt N]]
[[Category: Vielberg M-T]]
[[Category: Wolf F]]