5DZP

Crystal structure of Mycobacterium tuberculosis L,D-transpeptidase 2 with carbapenem drug T206 in conformation B

Summary for 5DZP

• Entry DOI: 10.2210/pdb5dzp/pdb
• Related: 5DZJ
• Descriptor: L,D-transpeptidase 2, (2~{R},3~{R},4~{R})-4-methyl-3-(2-oxidanylidene-2-propoxy-ethyl)sulfanyl-5-[(2~{S},3~{R})-3-oxidanyl-1-oxidanylidene-butan-2-yl]-3,4-dihydro-2~{H}-pyrrole-2-carboxylic acid (3 entities in total)
• Functional Keywords: peptidoglycan synthesis enzyme, cell wall enzyme, transferase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 2
• Total formula weight: 79409.42

Authors

Kumar, P.,Ginell, S.L.,Lamichhane, G. (deposition date: 2015-09-25, release date: 2016-10-05, Last modification date: 2023-09-27)

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 (2.19 Å)