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

DOI: 10.1016/j.str.2021.03.001 DOI Help

Authors: Anna York (University of Warwick) , Adrian J. Lloyd (University of Warwick) , Charo I. Del Genio (University of Coventry) , Jonathan Shearer (University of Southampton) , Karen J. Hinxman (University of Warwick) , Konstantin Fritz (University of Warwick) , Vilmos Fulop (University of Warwick) , Christopher G. Dowson (University of Warwick) , Syma Khalid (University of Southampton) , David I. Roper (University of Warwick; Columbia University Irving Medical Center)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Structure , VOL 1

State: Published (Approved)
Published: March 2021

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.

Journal Keywords: Streptococcus pneumoniae; MurM; penicillin resistance; peptidoglycan; indirect crosslinks; lipid bilayer; homology modeling; molecular dynamics; molecular docking

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 28/03/2021 11:12

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)