4mxi | pdb_00004mxi

ClpP Ser98dhA

spinqualitylabelsall models 4mxi, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4mxi is a 7 chain structure with sequence from Staphylococcus aureus subsp. aureus NCTC 8325. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: DHA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Clp protease 3D structures

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