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

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York, Anna, Lloyd, Adrian J., del Genio, Charo I., Shearer, Jonathan, Hinxman, Karen, Fritz, Konstantin, Fülöp, Vilmos, Dowson, Christopher G., Khalid, Syma and Roper, David I. (2021) Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane. Structure, 29 (7). pp. 731-742. doi:10.1016/j.str.2021.03.001

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Official URL: http://dx.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.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
Q Science > QR Microbiology
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Streptococcus pneumoniae , Penicillin resistance, Bacterial genetics , Cell membranes, Peptidoglycans -- Synthesis -- Mathematical models
Journal or Publication Title: Structure
Publisher: Cell Press
ISSN: 0969-2126
Official Date: 1 July 2021
Dates:
DateEvent
1 July 2021Published
18 March 2021Available
1 March 2021Accepted
Volume: 29
Number: 7
Page Range: pp. 731-742
DOI: 10.1016/j.str.2021.03.001
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
BB/J014532/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
EP/L015722/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
G1100127,[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0400848[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
MR/N002679/1 [MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/N003241/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268

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