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PLoS One. 2016 Mar 31;11(3):e0152075. doi: 10.1371/journal.pone.0152075. eCollection 2016.

Crystallographic Study of Peptidoglycan Biosynthesis Enzyme MurD: Domain Movement Revisited.

Author information

1
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, Ljubljana, Slovenia.
2
Lek Pharmaceuticals d. d., Verovškova 57, Ljubljana, Slovenia.
3
Laboratoire des Enveloppes Bactériennes et Antibiotiques, Institut de Biologie Intégrative de la Cellule (I2BC), CEA, CNRS, Université Paris-Sud, Gif-sur-Yvette, France.
4
Univ. Grenoble Alpes, Institut de Biologie Structurale, Grenoble, France.
5
CNRS, IBS, Grenoble, France.
6
CEA, IBS, Grenoble, France.
7
Brazilian National Laboratory for Biosciences (LNBio), CNPEM, Campinas, São Paulo, Brazil.

Abstract

The biosynthetic pathway of peptidoglycan, an essential component of bacterial cell wall, is a well-recognized target for antibiotic development. Peptidoglycan precursors are synthesized in the bacterial cytosol by various enzymes including the ATP-hydrolyzing Mur ligases, which catalyze the stepwise addition of amino acids to a UDP-MurNAc precursor to yield UDP-MurNAc-pentapeptide. MurD catalyzes the addition of D-glutamic acid to UDP-MurNAc-L-Ala in the presence of ATP; structural and biochemical studies have suggested the binding of the substrates with an ordered kinetic mechanism in which ligand binding inevitably closes the active site. In this work, we challenge this assumption by reporting the crystal structures of intermediate forms of MurD either in the absence of ligands or in the presence of small molecules. A detailed analysis provides insight into the events that lead to the closure of MurD and reveals that minor structural modifications contribute to major overall conformation alterations. These novel insights will be instrumental in the development of new potential antibiotics designed to target the peptidoglycan biosynthetic pathway.

PMID:
27031227
PMCID:
PMC4816537
DOI:
10.1371/journal.pone.0152075
[Indexed for MEDLINE]
Free PMC Article

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