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The role of the jaw subdomain of peptidoglycan glycosyltransferases for lipid II polymerization

The role of the jaw subdomain of peptidoglycan glycosyltransferases for lipid II polymerization
The role of the jaw subdomain of peptidoglycan glycosyltransferases for lipid II polymerization
Bacterial peptidoglycan glycosyltransferases (PGT) catalyse the essential polymerization of lipid II into linear glycan chains required for peptidoglycan biosynthesis. The PGT domain is composed of a large head subdomain and a smaller jaw subdomain and can be potently inhibited by the antibiotic moenomycin A (MoeA). We present an X-ray structure of the MoeA-bound Staphylococcus aureus monofunctional PGT enzyme, revealing electron density for a second MoeA bound to the jaw subdomain as well as the PGT donor site. Isothermal titration calorimetry confirms two drug-binding sites with markedly different affinities and positive cooperativity. Hydrophobic cluster analysis suggests that the membrane-interacting surface of the jaw subdomain has structural and physicochemical properties similar to amphipathic cationic α-helical antimicrobial peptides for lipid II recognition and binding. Furthermore, molecular dynamics simulations of the drug-free and -bound forms of the enzyme demonstrate the importance of the jaw subdomain movement for lipid II selection and polymerization process and provide molecular-level insights into the mechanism of peptidoglycan biosynthesis by PGTs.
Bacterial cell wall, Lipid II, Peptidoglycan synthesis, Glycosyltransferases, Jaw subdomain, Antibiotic resistance, Moenomycin A, Antimicrobial peptide
2468-2330
1-36
Punekar, Avinash S.
23b1961f-e154-4ba0-a971-bcb5a075f0ef
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Lloyd, Adrian J.
f91c1291-d23b-4436-bcc5-255c908a3527
Dowson, Christopher G
2d7d6f39-96da-4927-bea4-e25e80146b55
Scott, David J.
7fb13e85-4ba0-48cb-b131-17a865166651
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Roper, David I.
3fbc1c1e-9be3-4620-8e0b-f68c70cf054b
Punekar, Avinash S.
23b1961f-e154-4ba0-a971-bcb5a075f0ef
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Lloyd, Adrian J.
f91c1291-d23b-4436-bcc5-255c908a3527
Dowson, Christopher G
2d7d6f39-96da-4927-bea4-e25e80146b55
Scott, David J.
7fb13e85-4ba0-48cb-b131-17a865166651
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Roper, David I.
3fbc1c1e-9be3-4620-8e0b-f68c70cf054b

Punekar, Avinash S., Samsudin, Firdaus, Lloyd, Adrian J., Dowson, Christopher G, Scott, David J., Khalid, Syma and Roper, David I. (2018) The role of the jaw subdomain of peptidoglycan glycosyltransferases for lipid II polymerization. The Cell Surface, 1-36. (doi:10.1016/j.tcsw.2018.06.002).

Record type: Article

Abstract

Bacterial peptidoglycan glycosyltransferases (PGT) catalyse the essential polymerization of lipid II into linear glycan chains required for peptidoglycan biosynthesis. The PGT domain is composed of a large head subdomain and a smaller jaw subdomain and can be potently inhibited by the antibiotic moenomycin A (MoeA). We present an X-ray structure of the MoeA-bound Staphylococcus aureus monofunctional PGT enzyme, revealing electron density for a second MoeA bound to the jaw subdomain as well as the PGT donor site. Isothermal titration calorimetry confirms two drug-binding sites with markedly different affinities and positive cooperativity. Hydrophobic cluster analysis suggests that the membrane-interacting surface of the jaw subdomain has structural and physicochemical properties similar to amphipathic cationic α-helical antimicrobial peptides for lipid II recognition and binding. Furthermore, molecular dynamics simulations of the drug-free and -bound forms of the enzyme demonstrate the importance of the jaw subdomain movement for lipid II selection and polymerization process and provide molecular-level insights into the mechanism of peptidoglycan biosynthesis by PGTs.

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Accepted/In Press date: 12 June 2018
e-pub ahead of print date: 20 June 2018
Keywords: Bacterial cell wall, Lipid II, Peptidoglycan synthesis, Glycosyltransferases, Jaw subdomain, Antibiotic resistance, Moenomycin A, Antimicrobial peptide

Identifiers

Local EPrints ID: 421894
URI: http://eprints.soton.ac.uk/id/eprint/421894
ISSN: 2468-2330
PURE UUID: 54c5c418-a9f3-40b0-abe2-186cab41567d
ORCID for Firdaus Samsudin: ORCID iD orcid.org/0000-0003-2766-4459
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

Catalogue record

Date deposited: 06 Jul 2018 16:30
Last modified: 26 Nov 2021 03:05

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Contributors

Author: Avinash S. Punekar
Author: Firdaus Samsudin ORCID iD
Author: Adrian J. Lloyd
Author: Christopher G Dowson
Author: David J. Scott
Author: Syma Khalid ORCID iD
Author: David I. Roper

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