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

Avinash S Punekar, Firdaus Samsudin, Adrian J Lloyd, Christopher G Dowson, David J Scott, Syma Khalid, David I Roper

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
118 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)54-66
Number of pages13
JournalCell Surface
Publication statusPublished - Jun 2018


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