5E51

Crystal structure of Mycobacterium tuberculosis L,D-transpeptidase 1 with Faropenem adduct

Summary for 5E51

• Entry DOI: 10.2210/pdb5e51/pdb
• Descriptor: L,D-transpeptidase 1, (3R)-3-hydroxybutanal (3 entities in total)
• Functional Keywords: l, d-transpeptidase 1, peptidoglycan synthesis enzyme, cell wall enzyme, ldtmt1, mycobacterium tuberculosis, transferase
• Biological source: Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)
• Cellular location: Periplasm : Q7DAG3
• Total number of polymer chains: 4
• Total formula weight: 96044.07

Authors

Kumar, P.,Lamichhane, G.,Ginell, S.L. (deposition date: 2015-10-07, release date: 2016-10-26, Last modification date: 2024-11-20)

Primary citation

Kumar, P.,Kaushik, A.,Lloyd, E.P.,Li, S.G.,Mattoo, R.,Ammerman, N.C.,Bell, D.T.,Perryman, A.L.,Zandi, T.A.,Ekins, S.,Ginell, S.L.,Townsend, C.A.,Freundlich, J.S.,Lamichhane, G.
Non-classical transpeptidases yield insight into new antibacterials.
Nat. Chem. Biol., 13:54-61, 2017

PubMed Abstract: Bacterial survival requires an intact peptidoglycan layer, a three-dimensional exoskeleton that encapsulates the cytoplasmic membrane. Historically, the final steps of peptidoglycan synthesis are known to be carried out by D,D-transpeptidases, enzymes that are inhibited by the β-lactams, which constitute >50% of all antibacterials in clinical use. Here, we show that the carbapenem subclass of β-lactams are distinctly effective not only because they inhibit D,D-transpeptidases and are poor substrates for β-lactamases, but primarily because they also inhibit non-classical transpeptidases, namely the L,D-transpeptidases, which generate the majority of linkages in the peptidoglycan of mycobacteria. We have characterized the molecular mechanisms responsible for inhibition of L,D-transpeptidases of Mycobacterium tuberculosis and a range of bacteria including ESKAPE pathogens, and used this information to design, synthesize and test simplified carbapenems with potent antibacterial activity.

PubMed: 27820797
DOI: 10.1038/nchembio.2237

Experimental method

X-RAY DIFFRACTION (2.25 Å)