TY  - JOUR
AU  - Alves França, Bruno
AU  - Falke, Sven
AU  - Rohde, Holger
AU  - Betzel, Christian
TI  - Molecular insights into the dynamic modulation of bacterial ClpP function and oligomerization by peptidomimetic boronate compounds
JO  - Scientific reports
VL  - 14
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - PUBDB-2024-01690
SP  - 2572
PY  - 2024
AB  - Bacterial caseinolytic protease P subunit (ClpP) is important and vital for cell survival and infectivity. Recent publications describe and discuss the complex structure–function relationship of ClpP and its processive activity mediated by 14 catalytic sites. Even so, there are several aspects yet to be further elucidated, such as the paradoxical allosteric modulation of ClpP by peptidomimetic boronates. These compounds bind to all catalytic sites, and in specific conditions, they stimulate a dysregulated degradation of peptides and globular proteins, instead of inhibiting the enzymatic activity, as expected for serine proteases in general. Aiming to explore and explain this paradoxical effect, we solved and refined the crystal structure of native ClpP from Staphylococcus epidermidis (Se), an opportunistic pathogen involved in nosocomial infections, as well as ClpP in complex with ixazomib at 1.90 Å and 2.33 Å resolution, respectively. The interpretation of the crystal structures, in combination with complementary biochemical and biophysical data, shed light on how ixazomib affects the ClpP conformational state and activity. Moreover, SEC-SAXS and DLS measurements show, for the first time, that a peptidomimetic boronate compound also induces the assembly of the tetradecameric structure from isolated homomeric heptameric rings of a gram-positive organism.
LB  - PUB:(DE-HGF)16
C6  - pmid:38296985
UR  - <Go to ISI:>//WOS:001155680400031
DO  - DOI:10.1038/s41598-024-51787-0
UR  - https://bib-pubdb1.desy.de/record/606914
ER  -