Journal
STRUCTURE
Volume 29, Issue 7, Pages 731-+Publisher
CELL PRESS
DOI: 10.1016/j.str.2021.03.001
Keywords
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Funding
- Midlands Integrative Biosciences Training Partnership (MIBTP) BBSRC grant [BB/J014532/1]
- Center for Doctoral Training in Theory and Modeling in Chemical Sciences (TMCS DTC) EPSRC grant [EP/L015722/1]
- MRC [G1100127, G0400848, MR/N002679/1]
- BBSRC [BB/N003241/1]
- BBSRC [BB/N003241/1] Funding Source: UKRI
- MRC [G1100127] Funding Source: UKRI
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The study explored the interaction between MurM protein and membrane phospholipids, revealing that the activity of MurM is regulated by specific phospholipids. The spatial association of pneumococcal membrane phospholipids with MurM activity may play a critical role in the expression of penicillin resistance.
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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