4mxi: Difference between revisions
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== | ==ClpP Ser98dhA== | ||
[[http://www.uniprot.org/uniprot/CLPP_STAA8 CLPP_STAA8 | <StructureSection load='4mxi' size='340' side='right'caption='[[4mxi]], [[Resolution|resolution]] 2.30Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4mxi]] is a 7 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus_subsp._aureus_NCTC_8325 Staphylococcus aureus subsp. aureus NCTC 8325]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MXI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MXI 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]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DHA:2-AMINO-ACRYLIC+ACID'>DHA</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=4mxi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mxi OCA], [https://pdbe.org/4mxi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mxi RCSB], [https://www.ebi.ac.uk/pdbsum/4mxi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mxi ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[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;"> | |||
== Publication Abstract from PubMed == | |||
Over 100 protease inhibitors are currently used in the clinics and most of them use blockage of the active site for their mode of inhibition. Among the protease drug targets are several enzymes for which the correct multimeric assembly is crucial to their activity such as the proteasome and the HIV protease. Here, we present a novel mechanism of protease inhibition that relies on active-site-directed small molecules that disassemble the protease complex. We show the applicability of this mechanism within the ClpP protease family, whose members are tetradecameric serine proteases and serve as regulators of several cellular processes including homeostasis and virulence. Compound-binding to ClpP in substochiometric fashion triggers the formation of completely inactive heptamers. Moreover, we report the selective beta-sultam-induced dehydroalanine formation of the active site serine. This reaction proceeds through sulfonylation and subsequent elimination thereby obliterating the catalytic charge relay system. The identity of the dehydroalanine was confirmed by mass-spectrometry and crystallography. Activity-based protein profiling experiments suggest the formation of a dehydroalanine moiety in living S. aureus cells upon beta-sultam treatment. Collectively, these findings extend our view on multicomponent protease inhibition that until now has mainly relied on blockage of the active site or occupation of a regulatory allosteric site. | |||
Disruption of oligomerization and dehydroalanine formation as mechanisms for ClpP protease inhibition.,Gersch M, Kolb R, Alte F, Groll M, Sieber SA J Am Chem Soc. 2013 Oct 9. PMID:24106749<ref>PMID:24106749</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
< | </div> | ||
[[Category: | <div class="pdbe-citations 4mxi" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Alte | ==See Also== | ||
[[Category: Gersch | *[[Clp protease 3D structures|Clp protease 3D structures]] | ||
[[Category: Groll | == References == | ||
[[Category: Kolb | <references/> | ||
[[Category: Sieber | __TOC__ | ||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus subsp. aureus NCTC 8325]] | |||
[[Category: Alte F]] | |||
[[Category: Gersch M]] | |||
[[Category: Groll M]] | |||
[[Category: Kolb R]] | |||
[[Category: Sieber SA]] | |||
Latest revision as of 19:44, 20 September 2023
ClpP Ser98dhAClpP Ser98dhA
Structural highlights
FunctionCLPP_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 PubMedOver 100 protease inhibitors are currently used in the clinics and most of them use blockage of the active site for their mode of inhibition. Among the protease drug targets are several enzymes for which the correct multimeric assembly is crucial to their activity such as the proteasome and the HIV protease. Here, we present a novel mechanism of protease inhibition that relies on active-site-directed small molecules that disassemble the protease complex. We show the applicability of this mechanism within the ClpP protease family, whose members are tetradecameric serine proteases and serve as regulators of several cellular processes including homeostasis and virulence. Compound-binding to ClpP in substochiometric fashion triggers the formation of completely inactive heptamers. Moreover, we report the selective beta-sultam-induced dehydroalanine formation of the active site serine. This reaction proceeds through sulfonylation and subsequent elimination thereby obliterating the catalytic charge relay system. The identity of the dehydroalanine was confirmed by mass-spectrometry and crystallography. Activity-based protein profiling experiments suggest the formation of a dehydroalanine moiety in living S. aureus cells upon beta-sultam treatment. Collectively, these findings extend our view on multicomponent protease inhibition that until now has mainly relied on blockage of the active site or occupation of a regulatory allosteric site. Disruption of oligomerization and dehydroalanine formation as mechanisms for ClpP protease inhibition.,Gersch M, Kolb R, Alte F, Groll M, Sieber SA J Am Chem Soc. 2013 Oct 9. PMID:24106749[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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