Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane

Anna York; Adrian J Lloyd; Charo I del Genio; Jonathan Shearer; Karen J Hinxman; Konstantin Fritz; Vilmos Fulop; Christopher G Dowson; Syma Khalid; David I Roper

doi:10.1016/j.str.2021.03.001

Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane

Anna York, Adrian J Lloyd, Charo I del Genio, Jonathan Shearer, Karen J Hinxman, Konstantin Fritz, Vilmos Fulop, Christopher G Dowson, Syma Khalid, David I Roper

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Abstract

Branched Lipid II, required for the formation of indirectly crosslinked peptidoglycan, is generated by MurM, a protein essential for high-level penicillin resistance in the human pathogen Streptococcus pneumoniae. We have solved the X-ray crystal structure of Staphylococcus aureus FemX, an isofunctional homolog, and have used this as a template to generate a MurM homology model. Using this model, we perform molecular docking and molecular dynamics to examine the interaction of MurM with the phospholipid bilayer and the membrane-embedded Lipid II substrate. Our model suggests that MurM is associated with the major membrane phospholipid cardiolipin, and experimental evidence confirms that the activity of MurM is enhanced by this phospholipid and inhibited by its direct precursor phosphatidylglycerol. The spatial association of pneumococcal membrane phospholipids and their impact on MurM activity may therefore be critical to the final architecture of peptidoglycan and the expression of clinically relevant penicillin resistance in this pathogen.

Original language	English
Article number	1
Pages (from-to)	731-742.e6
Journal	Structure
Volume	29
Issue number	7
Early online date	18 Mar 2021
DOIs	https://doi.org/10.1016/j.str.2021.03.001
Publication status	Published - 1 Jul 2021

Bibliographical note

NOTICE: this is the author’s version of a work that was accepted for publication in Structure. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Structure, 7:1, (2021) DOI: 10.1016/j.str.2021.03.001

© 2021, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

Funder

This research was supported in part by the Midlands Integrative Biosciences Training Partnership (MIBTP) BBSRC grant BB/J014532/1, and the Center for Doctoral Training in Theory and Modeling in Chemical Sciences (TMCS DTC) EPSRC grant EP/L015722/1, as well as MRC grants G1100127, G0400848, MR/N002679/1 and BBSRC grant BB/N003241/1.

Keywords

Streptococcus pneumoniae
MurM
penicillin resistance
peptidoglycan
indirect crosslinks
lipid bilayer
homology modeling
molecular dynamics
molecular docking

ASJC Scopus subject areas

Molecular Biology

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10.1016/j.str.2021.03.001

Post-PrintAccepted author manuscript, 4.1 MBLicence: CC BY-NC-ND

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York, A., Lloyd, A. J., del Genio, C. I., Shearer, J., Hinxman, K. J., Fritz, K., Fulop, V., Dowson, C. G., Khalid, S., & Roper, D. I. (2021). Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane. Structure, 29(7), 731-742.e6. Article 1. https://doi.org/10.1016/j.str.2021.03.001

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abstract = "Branched Lipid II, required for the formation of indirectly crosslinked peptidoglycan, is generated by MurM, a protein essential for high-level penicillin resistance in the human pathogen Streptococcus pneumoniae. We have solved the X-ray crystal structure of Staphylococcus aureus FemX, an isofunctional homolog, and have used this as a template to generate a MurM homology model. Using this model, we perform molecular docking and molecular dynamics to examine the interaction of MurM with the phospholipid bilayer and the membrane-embedded Lipid II substrate. Our model suggests that MurM is associated with the major membrane phospholipid cardiolipin, and experimental evidence confirms that the activity of MurM is enhanced by this phospholipid and inhibited by its direct precursor phosphatidylglycerol. The spatial association of pneumococcal membrane phospholipids and their impact on MurM activity may therefore be critical to the final architecture of peptidoglycan and the expression of clinically relevant penicillin resistance in this pathogen.",

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AU - Hinxman, Karen J

AU - Fritz, Konstantin

AU - Fulop, Vilmos

AU - Dowson, Christopher G

AU - Khalid, Syma

AU - Roper, David I

N1 - NOTICE: this is the author’s version of a work that was accepted for publication in Structure. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Structure, 7:1, (2021) DOI: 10.1016/j.str.2021.03.001 © 2021, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

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N2 - Branched Lipid II, required for the formation of indirectly crosslinked peptidoglycan, is generated by MurM, a protein essential for high-level penicillin resistance in the human pathogen Streptococcus pneumoniae. We have solved the X-ray crystal structure of Staphylococcus aureus FemX, an isofunctional homolog, and have used this as a template to generate a MurM homology model. Using this model, we perform molecular docking and molecular dynamics to examine the interaction of MurM with the phospholipid bilayer and the membrane-embedded Lipid II substrate. Our model suggests that MurM is associated with the major membrane phospholipid cardiolipin, and experimental evidence confirms that the activity of MurM is enhanced by this phospholipid and inhibited by its direct precursor phosphatidylglycerol. The spatial association of pneumococcal membrane phospholipids and their impact on MurM activity may therefore be critical to the final architecture of peptidoglycan and the expression of clinically relevant penicillin resistance in this pathogen.

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Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane

Abstract

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Keywords

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