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Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane.
York, Anna; Lloyd, Adrian J; Del Genio, Charo I; Shearer, Jonathan; Hinxman, Karen J; Fritz, Konstantin; Fulop, Vilmos; Dowson, Christopher G; Khalid, Syma; Roper, David I.
Afiliação
  • York A; School of Life Science, University of Warwick, Coventry, West Midlands CV4 7AL, UK.
  • Lloyd AJ; School of Life Science, University of Warwick, Coventry, West Midlands CV4 7AL, UK.
  • Del Genio CI; Centre for Fluid and Complex Systems, School of Computing, Electronics and Mathematics, University of Coventry, West Midlands CV1 5FB, UK.
  • Shearer J; School of Chemistry, University of Southampton, Southampton, Hampshire SO17 1BJ, UK.
  • Hinxman KJ; School of Life Science, University of Warwick, Coventry, West Midlands CV4 7AL, UK.
  • Fritz K; School of Life Science, University of Warwick, Coventry, West Midlands CV4 7AL, UK.
  • Fulop V; School of Life Science, University of Warwick, Coventry, West Midlands CV4 7AL, UK.
  • Dowson CG; School of Life Science, University of Warwick, Coventry, West Midlands CV4 7AL, UK.
  • Khalid S; School of Chemistry, University of Southampton, Southampton, Hampshire SO17 1BJ, UK. Electronic address: s.khalid@soton.ac.uk.
  • Roper DI; School of Life Science, University of Warwick, Coventry, West Midlands CV4 7AL, UK; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. Electronic address: david.roper@warwick.ac.uk.
Structure ; 29(7): 731-742.e6, 2021 07 01.
Article em En | MEDLINE | ID: mdl-33740396
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeo Sintases / Streptococcus pneumoniae / Proteínas de Bactérias / Resistência às Penicilinas / Cardiolipinas Idioma: En Revista: Structure Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Peptídeo Sintases / Streptococcus pneumoniae / Proteínas de Bactérias / Resistência às Penicilinas / Cardiolipinas Idioma: En Revista: Structure Assunto da revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Ano de publicação: 2021 Tipo de documento: Article