View source for 6l40


==Discovery of novel peptidomimetic boronate ClpP inhibitors with noncanonical enzyme mechanism as potent virulence blockers in vitro and in vivo==
<StructureSection load='6l40' size='340' side='right'caption='[[6l40]], [[Resolution|resolution]] 2.21&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6l40]] is a 14 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_RF122 Staphylococcus aureus RF122]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6L40 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6L40 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]] 2.209&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FN3:[(1S)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazin-2-ylcarbonylamino)propanoyl]amino]butyl]boronic+acid'>FN3</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=6l40 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6l40 OCA], [https://pdbe.org/6l40 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6l40 RCSB], [https://www.ebi.ac.uk/pdbsum/6l40 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6l40 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/CLPP_STAAB CLPP_STAAB] 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.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.

Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo.,Ju Y, He L, Zhou Y, Yang T, Sun K, Song R, Yang Y, Li C, Sang Z, Bao R, Luo Y J Med Chem. 2020 Mar 26;63(6):3104-3119. doi: 10.1021/acs.jmedchem.9b01746. Epub , 2020 Feb 20. PMID:32031798<ref>PMID:32031798</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6l40" style="background-color:#fffaf0;"></div>

==See Also==
*[[Clp protease 3D structures|Clp protease 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Staphylococcus aureus RF122]]
[[Category: Bao R]]
[[Category: He LH]]
[[Category: Ju Y]]
[[Category: Luo YF]]