ClpP protease activation results from the reorganization of the electrostatic interaction networks at the entrance pores
| Autor: | Siavash Vahidi, Elisa Leung, Emil F. Pai, Bryan T. Eger, Sadhna Phanse, Yu-Qian Mao, Vaibhav Bhandari, Mark F. Mabanglo, Jin Lin Zhou, Marim M Barghash, Robert A. Batey, Mohan Babu, Kamran Rizzolo, Thiago V. Seraphim, Steve Bryson, Walid A. Houry, Carlos H.I. Ramos, Lewis E. Kay, Leandro R.S. Barbosa, Jordan D. Goodreid |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular 0301 basic medicine Proteases Magnetic Resonance Spectroscopy medicine.medical_treatment Static Electricity Medicine (miscellaneous) Molecular Dynamics Simulation Crystallography X-Ray medicine.disease_cause 01 natural sciences Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Hydrolase medicine Amino Acid Sequence lcsh:QH301-705.5 Escherichia coli X-ray crystallography Serine protease Binding Sites Protease biology 010405 organic chemistry Activator (genetics) Chemistry CRISTALOGRAFIA DE RAIOS X Endopeptidase Clp Small molecule 0104 chemical sciences Enzyme Activation Molecular Docking Simulation 030104 developmental biology Proteostasis lcsh:Biology (General) Biophysics biology.protein Protein Tyrosine Phosphatases General Agricultural and Biological Sciences Protein Binding |
| Zdroj: | Communications Biology Communications Biology, Vol 2, Iss 1, Pp 1-14 (2019) Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 2399-3642 |
| DOI: | 10.1038/s42003-019-0656-3 |
| Popis: | Bacterial ClpP is a highly conserved, cylindrical, self-compartmentalizing serine protease required for maintaining cellular proteostasis. Small molecule acyldepsipeptides (ADEPs) and activators of self-compartmentalized proteases 1 (ACP1s) cause dysregulation and activation of ClpP, leading to bacterial cell death, highlighting their potential use as novel antibiotics. Structural changes in Neisseria meningitidis and Escherichia coli ClpP upon binding to novel ACP1 and ADEP analogs were probed by X-ray crystallography, methyl-TROSY NMR, and small angle X-ray scattering. ACP1 and ADEP induce distinct conformational changes in the ClpP structure. However, reorganization of electrostatic interaction networks at the ClpP entrance pores is necessary and sufficient for activation. Further activation is achieved by formation of ordered N-terminal axial loops and reduction in the structural heterogeneity of the ClpP cylinder. Activating mutations recapitulate the structural effects of small molecule activator binding. Our data, together with previous findings, provide a structural basis for a unified mechanism of compound-based ClpP activation. Mabanglo, Leung, Vahidi, Seraphim et al. examine the structural changes to ClpP from Neisseria meningitidis and Escherichia coli upon binding to two novel activators. They show that reorganization of the electrostatic interaction networks at the ClpP entrance pores is needed for activation. |
| Databáze: | OpenAIRE |
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