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

Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane
Structure-based modeling and dynamics of MurM, a Streptococcus pneumoniae penicillin resistance determinant present at the cytoplasmic membrane
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.
MurM, Streptococcus pneumoniae, homology modeling, indirect crosslinks, lipid bilayer, molecular docking, molecular dynamics, penicillin resistance, peptidoglycan
0969-2126
731-742
York, Anna
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Lloyd, Adrian J.
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del Genio, Charo I.
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Shearer, Jonathan
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Hinxman, Karen.J.
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Fritz, Konstantin
df91d4cb-19b8-4ea5-8c32-2e2fafc4a236
Fulop, Vilmos
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Dowson, Christopher.G.
eb302048-ec10-49fd-905f-cffbe39b10a8
Khalid, Syma
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Roper, David I.
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York, Anna
811db4f2-a92f-4ff4-9350-6329ebbdead8
Lloyd, Adrian J.
f91c1291-d23b-4436-bcc5-255c908a3527
del Genio, Charo I.
dce1c697-7abb-4237-af76-b7ce5aa8df5a
Shearer, Jonathan
44810f0c-f875-465e-be3b-810155814bc5
Hinxman, Karen.J.
24edbd67-9ee3-4190-9678-1f2e7ff8b8b5
Fritz, Konstantin
df91d4cb-19b8-4ea5-8c32-2e2fafc4a236
Fulop, Vilmos
9415cbe4-b915-44cf-a49b-b99771ae662e
Dowson, Christopher.G.
eb302048-ec10-49fd-905f-cffbe39b10a8
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Roper, David I.
3fbc1c1e-9be3-4620-8e0b-f68c70cf054b

York, Anna, Lloyd, Adrian J., del Genio, Charo I., Shearer, Jonathan, Hinxman, Karen.J., Fritz, Konstantin, Fulop, 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), 731-742. (doi:10.1016/j.str.2021.03.001).

Record type: Article

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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STRUCTURE-D-20-00141_R2-part 1 - Accepted Manuscript
Restricted to Repository staff only until 1 July 2022.
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Accepted/In Press date: 1 March 2021
Published date: 1 July 2021
Additional Information: Funding Information: 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 . The authors would like to acknowledge the help of the Media Preparation Facility in the School of Life Sciences at the University of Warwick. We would also like to thank Dr Allister Crow for his help and support with using PyMOL. Funding Information: 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. The authors would like to acknowledge the help of the Media Preparation Facility in the School of Life Sciences at the University of Warwick. We would also like to thank Dr Allister Crow for his help and support with using PyMOL. Conceptualization, A.Y. A.J.L. D.I.R. and S.K.; Investigation, K.F. K.J.H. V.F. A.J.L. A.Y. J.S. and C.I.d.G.; Methodology/software/formal analysis, C.I.d.G. J.S. A.Y. and S.K.; Writing ? original draft, A.Y. J.S. and C.I.d.G.; Writing ? review & editing, A.Y. A.J.L. S.K. D.I.R. and C.G.D.; Funding acquisition, A.Y. J.S. and C.G.D.; Supervision, A.J.L. D.I.R. S.K. and C.G.D.; Project administration, A.Y.; Visualization, A.Y. A.J.L. J.S. and S.K. The authors declare no competing interests. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
Keywords: MurM, Streptococcus pneumoniae, homology modeling, indirect crosslinks, lipid bilayer, molecular docking, molecular dynamics, penicillin resistance, peptidoglycan

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Local EPrints ID: 450399
URI: http://eprints.soton.ac.uk/id/eprint/450399
ISSN: 0969-2126
PURE UUID: c6bddff4-6573-4ad5-8b90-1676d996a7cd
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

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Date deposited: 27 Jul 2021 17:23
Last modified: 28 Jul 2021 01:40

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Contributors

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

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