4MXI

ClpP Ser98dhA

Summary for 4MXI

• Entry DOI: 10.2210/pdb4mxi/pdb
• Related: 3QWD 3V5E 3V5I
• Descriptor: ATP-dependent Clp protease proteolytic subunit (2 entities in total)
• Functional Keywords: serine protease, clpp, inhibition, complex disassembly, dehydroalanine, hydrolase
• Biological source: Staphylococcus aureus subsp. aureus
• Cellular location: Cytoplasm (By similarity): Q2G036
• Total number of polymer chains: 7
• Total formula weight: 150629.61

Authors

Gersch, M.,Kolb, R.,Alte, F.,Groll, M.,Sieber, S.A. (deposition date: 2013-09-26, release date: 2013-10-23, Last modification date: 2023-09-20)

Primary citation

Gersch, M.,Kolb, R.,Alte, F.,Groll, M.,Sieber, S.A.
Disruption of Oligomerization and Dehydroalanine Formation as Mechanisms for ClpP Protease Inhibition.
J.Am.Chem.Soc., 136:1360-1366, 2014

PubMed Abstract: 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 a substoichiometric fashion triggers the formation of completely inactive heptamers. Moreover, we report the selective β-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 β-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.

PubMed: 24106749
DOI: 10.1021/ja4082793

Experimental method

X-RAY DIFFRACTION (2.3 Å)