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Structural and functional analysis of the d-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50

d-Alanylation of the teichoic acids of the Gram-positive bacterial cell wall plays crucial roles in bacterial physiology and virulence. Deprivation of d-alanine from the teichoic acids of Staphylococcus aureus impairs biofilm and colony formation, induces autolysis and ultimately renders methicillin...

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Autores principales: Lee, In-Gyun, Song, Chiman, Yang, Seoyeong, Jeon, Hanul, Park, Jingyeong, Yoon, Hye-Jin, Im, Hookang, Kang, Sung-Min, Eun, Hyun-Jong, Lee, Bong-Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: International Union of Crystallography 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972799/
https://www.ncbi.nlm.nih.gov/pubmed/35362466
http://dx.doi.org/10.1107/S2059798322000547
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author Lee, In-Gyun
Song, Chiman
Yang, Seoyeong
Jeon, Hanul
Park, Jingyeong
Yoon, Hye-Jin
Im, Hookang
Kang, Sung-Min
Eun, Hyun-Jong
Lee, Bong-Jin
author_facet Lee, In-Gyun
Song, Chiman
Yang, Seoyeong
Jeon, Hanul
Park, Jingyeong
Yoon, Hye-Jin
Im, Hookang
Kang, Sung-Min
Eun, Hyun-Jong
Lee, Bong-Jin
author_sort Lee, In-Gyun
collection PubMed
description d-Alanylation of the teichoic acids of the Gram-positive bacterial cell wall plays crucial roles in bacterial physiology and virulence. Deprivation of d-alanine from the teichoic acids of Staphylococcus aureus impairs biofilm and colony formation, induces autolysis and ultimately renders methicillin-resistant S. aureus highly susceptible to antimicrobial agents and host defense peptides. Hence, the d-alanylation pathway has emerged as a promising antibacterial target against drug-resistant S. aureus. d-Alanylation of teichoic acids is mediated via the action of four proteins encoded by the dlt operon, DltABCD, all four of which are essential for the process. In order to develop novel antimicrobial agents against S. aureus, the d-alanyl carrier protein ligase DltA, which is the first protein in the d-alanylation pathway, was focused on. Here, the crystal structure of DltA from the methicillin-resistant S. aureus strain Mu50 is presented, which reveals the unique molecular details of the catalytic center and the role of the P-loop. Kinetic analysis shows that the enantioselectivity of S. aureus DltA is much higher than that of DltA from other species. In the presence of DltC, the enzymatic activity of DltA is increased by an order of magnitude, suggesting a new exploitable binding pocket. This discovery may pave the way for a new generation of treatments for drug-resistant S. aureus.
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spelling pubmed-89727992022-04-28 Structural and functional analysis of the d-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50 Lee, In-Gyun Song, Chiman Yang, Seoyeong Jeon, Hanul Park, Jingyeong Yoon, Hye-Jin Im, Hookang Kang, Sung-Min Eun, Hyun-Jong Lee, Bong-Jin Acta Crystallogr D Struct Biol Research Papers d-Alanylation of the teichoic acids of the Gram-positive bacterial cell wall plays crucial roles in bacterial physiology and virulence. Deprivation of d-alanine from the teichoic acids of Staphylococcus aureus impairs biofilm and colony formation, induces autolysis and ultimately renders methicillin-resistant S. aureus highly susceptible to antimicrobial agents and host defense peptides. Hence, the d-alanylation pathway has emerged as a promising antibacterial target against drug-resistant S. aureus. d-Alanylation of teichoic acids is mediated via the action of four proteins encoded by the dlt operon, DltABCD, all four of which are essential for the process. In order to develop novel antimicrobial agents against S. aureus, the d-alanyl carrier protein ligase DltA, which is the first protein in the d-alanylation pathway, was focused on. Here, the crystal structure of DltA from the methicillin-resistant S. aureus strain Mu50 is presented, which reveals the unique molecular details of the catalytic center and the role of the P-loop. Kinetic analysis shows that the enantioselectivity of S. aureus DltA is much higher than that of DltA from other species. In the presence of DltC, the enzymatic activity of DltA is increased by an order of magnitude, suggesting a new exploitable binding pocket. This discovery may pave the way for a new generation of treatments for drug-resistant S. aureus. International Union of Crystallography 2022-03-16 /pmc/articles/PMC8972799/ /pubmed/35362466 http://dx.doi.org/10.1107/S2059798322000547 Text en © In-Gyun Lee et al. 2022 https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.
spellingShingle Research Papers
Lee, In-Gyun
Song, Chiman
Yang, Seoyeong
Jeon, Hanul
Park, Jingyeong
Yoon, Hye-Jin
Im, Hookang
Kang, Sung-Min
Eun, Hyun-Jong
Lee, Bong-Jin
Structural and functional analysis of the d-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50
title Structural and functional analysis of the d-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50
title_full Structural and functional analysis of the d-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50
title_fullStr Structural and functional analysis of the d-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50
title_full_unstemmed Structural and functional analysis of the d-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50
title_short Structural and functional analysis of the d-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50
title_sort structural and functional analysis of the d-alanyl carrier protein ligase dlta from staphylococcus aureus mu50
topic Research Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8972799/
https://www.ncbi.nlm.nih.gov/pubmed/35362466
http://dx.doi.org/10.1107/S2059798322000547
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