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Title: Acyldepsipeptide Antibiotics Induce the Formation of a Structured Axial Channel in ClpP: A Model for the ClpX/ClpA-Bound State of ClpP

Abstract

In ClpXP and ClpAP complexes, ClpA and ClpX use the energy of ATP hydrolysis to unfold proteins and translocate them into the self-compartmentalized ClpP protease. ClpP requires the ATPases to degrade folded or unfolded substrates, but binding of acyldepsipeptide antibiotics (ADEPs) to ClpP bypasses this requirement with unfolded proteins. We present the crystal structure of Escherichia coli ClpP bound to ADEP1 and report the structural changes underlying ClpP activation. ADEP1 binds in the hydrophobic groove that serves as the primary docking site for ClpP ATPases. Binding of ADEP1 locks the N-terminal loops of ClpP in a {beta}-hairpin conformation, generating a stable pore through which extended polypeptides can be threaded. This structure serves as a model for ClpP in the holoenzyme ClpAP and ClpXP complexes and provides critical information to further develop this class of antibiotics.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
DOE - OFFICE OF SCIENCE
OSTI Identifier:
1019727
Report Number(s):
BNL-95573-2011-JA
Journal ID: ISSN 1074-5521; TRN: US201115%%366
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Chemistry and Biology
Additional Journal Information:
Journal Volume: 17; Journal Issue: 9; Journal ID: ISSN 1074-5521
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ANTIBIOTICS; CRYSTAL STRUCTURE; ESCHERICHIA COLI; HYDROLYSIS; POLYPEPTIDES; PROTEINS; SUBSTRATES; national synchrotron light source

Citation Formats

Li, D., Chung, Y, Gloyd, M, Joseph, E, Ghirlando, R, Wright, G, Cheng, Y, Maurizi, M, Guarne, A, and Ortega, J. Acyldepsipeptide Antibiotics Induce the Formation of a Structured Axial Channel in ClpP: A Model for the ClpX/ClpA-Bound State of ClpP. United States: N. p., 2010. Web. doi:10.1016/j.chembiol.2010.07.008.
Li, D., Chung, Y, Gloyd, M, Joseph, E, Ghirlando, R, Wright, G, Cheng, Y, Maurizi, M, Guarne, A, & Ortega, J. Acyldepsipeptide Antibiotics Induce the Formation of a Structured Axial Channel in ClpP: A Model for the ClpX/ClpA-Bound State of ClpP. United States. doi:10.1016/j.chembiol.2010.07.008.
Li, D., Chung, Y, Gloyd, M, Joseph, E, Ghirlando, R, Wright, G, Cheng, Y, Maurizi, M, Guarne, A, and Ortega, J. Fri . "Acyldepsipeptide Antibiotics Induce the Formation of a Structured Axial Channel in ClpP: A Model for the ClpX/ClpA-Bound State of ClpP". United States. doi:10.1016/j.chembiol.2010.07.008.
@article{osti_1019727,
title = {Acyldepsipeptide Antibiotics Induce the Formation of a Structured Axial Channel in ClpP: A Model for the ClpX/ClpA-Bound State of ClpP},
author = {Li, D. and Chung, Y and Gloyd, M and Joseph, E and Ghirlando, R and Wright, G and Cheng, Y and Maurizi, M and Guarne, A and Ortega, J},
abstractNote = {In ClpXP and ClpAP complexes, ClpA and ClpX use the energy of ATP hydrolysis to unfold proteins and translocate them into the self-compartmentalized ClpP protease. ClpP requires the ATPases to degrade folded or unfolded substrates, but binding of acyldepsipeptide antibiotics (ADEPs) to ClpP bypasses this requirement with unfolded proteins. We present the crystal structure of Escherichia coli ClpP bound to ADEP1 and report the structural changes underlying ClpP activation. ADEP1 binds in the hydrophobic groove that serves as the primary docking site for ClpP ATPases. Binding of ADEP1 locks the N-terminal loops of ClpP in a {beta}-hairpin conformation, generating a stable pore through which extended polypeptides can be threaded. This structure serves as a model for ClpP in the holoenzyme ClpAP and ClpXP complexes and provides critical information to further develop this class of antibiotics.},
doi = {10.1016/j.chembiol.2010.07.008},
journal = {Chemistry and Biology},
issn = {1074-5521},
number = 9,
volume = 17,
place = {United States},
year = {2010},
month = {1}
}