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Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics

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Harvard

Crowe-McAuliffe, C, Murina, V, Turnbull, KJ, Huch, S, Kasari, M, Takada, H, Nersisyan, L, Sundsfjord, A, Hegstad, K, Atkinson, GC, Pelechano, V, Wilson, DN & Hauryliuk, V 2022, 'Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics', Nature Communications, bind 13, nr. 1, 1860. https://doi.org/10.1038/s41467-022-29274-9

APA

Crowe-McAuliffe, C., Murina, V., Turnbull, K. J., Huch, S., Kasari, M., Takada, H., Nersisyan, L., Sundsfjord, A., Hegstad, K., Atkinson, G. C., Pelechano, V., Wilson, D. N., & Hauryliuk, V. (2022). Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics. Nature Communications, 13(1), [1860]. https://doi.org/10.1038/s41467-022-29274-9

CBE

Crowe-McAuliffe C, Murina V, Turnbull KJ, Huch S, Kasari M, Takada H, Nersisyan L, Sundsfjord A, Hegstad K, Atkinson GC, Pelechano V, Wilson DN, Hauryliuk V. 2022. Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics. Nature Communications. 13(1):Article 1860. https://doi.org/10.1038/s41467-022-29274-9

MLA

Vancouver

Author

Crowe-McAuliffe, Caillan ; Murina, Victoriia ; Turnbull, Kathryn Jane ; Huch, Susanne ; Kasari, Marje ; Takada, Hiraku ; Nersisyan, Lilit ; Sundsfjord, Arnfinn ; Hegstad, Kristin ; Atkinson, Gemma C. ; Pelechano, Vicent ; Wilson, Daniel N. ; Hauryliuk, Vasili. / Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics. I: Nature Communications. 2022 ; Bind 13, Nr. 1.

Bibtex

@article{79a901aa16654530be021cba64118f6a,
title = "Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics",
abstract = "PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 {\AA} out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.",
author = "Caillan Crowe-McAuliffe and Victoriia Murina and Turnbull, {Kathryn Jane} and Susanne Huch and Marje Kasari and Hiraku Takada and Lilit Nersisyan and Arnfinn Sundsfjord and Kristin Hegstad and Atkinson, {Gemma C.} and Vicent Pelechano and Wilson, {Daniel N.} and Vasili Hauryliuk",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-29274-9",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1722",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics

AU - Crowe-McAuliffe, Caillan

AU - Murina, Victoriia

AU - Turnbull, Kathryn Jane

AU - Huch, Susanne

AU - Kasari, Marje

AU - Takada, Hiraku

AU - Nersisyan, Lilit

AU - Sundsfjord, Arnfinn

AU - Hegstad, Kristin

AU - Atkinson, Gemma C.

AU - Pelechano, Vicent

AU - Wilson, Daniel N.

AU - Hauryliuk, Vasili

N1 - Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Å out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.

AB - PoxtA and OptrA are ATP binding cassette (ABC) proteins of the F subtype (ABCF). They confer resistance to oxazolidinone and phenicol antibiotics, such as linezolid and chloramphenicol, which stall translating ribosomes when certain amino acids are present at a defined position in the nascent polypeptide chain. These proteins are often encoded on mobile genetic elements, facilitating their rapid spread amongst Gram-positive bacteria, and are thought to confer resistance by binding to the ribosome and dislodging the bound antibiotic. However, the mechanistic basis of this resistance remains unclear. Here we refine the PoxtA spectrum of action, demonstrate alleviation of linezolid-induced context-dependent translational stalling, and present cryo-electron microscopy structures of PoxtA in complex with the Enterococcus faecalis 70S ribosome. PoxtA perturbs the CCA-end of the P-site tRNA, causing it to shift by ∼4 Å out of the ribosome, corresponding to a register shift of approximately one amino acid for an attached nascent polypeptide chain. We postulate that the perturbation of the P-site tRNA by PoxtA thereby alters the conformation of the attached nascent chain to disrupt the drug binding site.

UR - http://www.scopus.com/inward/record.url?scp=85127639432&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-29274-9

DO - 10.1038/s41467-022-29274-9

M3 - Journal article

C2 - 35387982

AN - SCOPUS:85127639432

VL - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1722

IS - 1

M1 - 1860

ER -

ID: 79408604