5K69

Crystal structure of Mycobacterium tuberculosis L,D-transpeptidase 2 with carbapenem drug T224

Summary for 5K69

• Entry DOI: 10.2210/pdb5k69/pdb
• Descriptor: L,D-transpeptidase 2, GLYCEROL, (2~{S},3~{R},4~{R})-4-(1~{H}-indol-3-ylsulfanyl)-3-methyl-2-[(2~{S},3~{S})-3-oxidanyl-1-oxidanylidene-butan-2-yl]-3,4-dihydro-2~{H}-pyrrole-5-carboxylic acid, ... (4 entities in total)
• Functional Keywords: peptidase, igd_like domain, ykud domain, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 2
• Total formula weight: 87812.56

Authors

Lamichhane, G.,Ginell, S.L.,Kumar, P. (deposition date: 2016-05-24, release date: 2016-11-09, Last modification date: 2024-11-06)

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 (2.001 Å)