Tailored Peptide Phenyl Esters Block ClpXP Proteolysis by an Unusual Breakdown into a Heptamer-Hexamer Assembly

被引：9

作者：

Lakemeyer, Markus ^{[1
]}

Bertosin, Eva ^{[2
,3
]}

Moeller, Friederike ^{[4
]}

Balogh, Dora ^{[1
]}

Strasser, Ralf ^{[4
]}

Dietz, Hendrik ^{[2
,3
]}

Sieber, Stephan A. ^{[1
]}

机构：

[1] Tech Univ Munich, Dept Chem, Ctr Integrated Prot Sci CIPSM, Lichtenbergstr 4, D-85747 Garching, Germany

[2] Tech Univ Munich, Phys Dept, Coulombwall 4a, D-85748 Garching, Germany

[3] Tech Univ Munich, Inst Adv Study, Coulombwall 4a, D-85748 Garching, Germany

[4] Dynam Biosensors GmbH, Lochhamerstr 15, D-82152 Planegg, Germany

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2019年 / 58卷 / 21期

关键词：

activation; caseinolytic proteases; conformational selection; inhibitors; structure-activity relationships; CASEINOLYTIC PROTEASE P; CHAPERONE AFFINITY; INHIBITORS; VIRULENCE; OLIGOMERIZATION; ACTIVATION; INSIGHTS; REVEAL;

D O I：

10.1002/anie.201901056

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

The proteolytic complex ClpXP is fundamental to bacterial homeostasis and pathogenesis. Because of its conformational flexibility, the development of potent ClpXP inhibitors is challenging, and novel tools to decipher its intricate regulation are urgently needed. Herein, we present amino acid based phenyl esters as molecular probes to study the activity and oligomerization of the ClpXP complex of S.aureus. Systematic screening of (R)- and (S)-amino acids led to compounds showing potent inhibition, as well as stimulation of ClpXP-mediated proteolysis. Substoichiometric binding of probes arrested ClpXP in an unprecedented heptamer-hexamer assembly, in which the two heptameric ClpP rings are dissociated from each other. At the same time, the affinity between ClpX and ClpP increased, leading to inhibition of both enzymes. This conformational arrest is beneficial for the consolidated shutdown of ClpXP, as well as for the study of the oligomeric state during its catalytic cycle.

引用

页码：7127 / 7132

页数：6