Structural basis for the inhibition of Mycobacterium tuberculosis l,d-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains

Kim, H.S.; Kim, J.; Im, H.N.; Yoon, J.Y.; An, D.R.; Yoon, H.J.; Kim, J.Y.; Min, H.K.; Kim, S.-J.; Lee, J.Y.; Han, B.W.; Suh, S.W.

doi:10.1107/S0907444912048998

Figure 4
The active site of the Ldt domain and the substrate-binding sites. (a) Active-site superposition of the apo (orange), mercury-derivatized (magenta) and meropenem-complexed (chain B, cyan) Ldt_Mt2Δ130. Dotted lines denote interactions: hydrogen bonds to the catalytic triad (red) and the oxyanion hole (green), Ser351 with the oxyanion hole (black), His336 with Asn356 (black) and His352 with Cys354 S^γ and the main-chain carbonyl O atom of His352 in the mercury-derivatized model (purple). The covalently bound meropenem adduct in the meropenem complex is shown as a stick model. (b) Active-site superposition of meropenem-complexed Ldt_Mt2 (chain B, cyan), Ldt_Bs (green) and Ldt_fm (grey) in the same view as in (a). (c, d) Electrostatic surface representations of the predicted binding sites for the donor substrate in the open conformation of mercury-derivatized Ldt_Mt2Δ130 (c) and the acceptor substrate in the closed conformation of meropenem-complexed Ldt_Mt2Δ130 (d) coloured as in Fig. 1

(d). The surfaces of the binding site are represented with constituent residues as stick models. The movement of the imidazole ring of His352 in the apo form (orange) and the mercury-derivatized form (magenta) is presented in stick models with dotted surfaces in (c). The peptide bond of the donor substrate (meso-DAP³-D-Ala⁴) is schematically modelled into the active site in the open conformation. The terminus of the acceptor substrate (meso-DAP³) is schematically modelled into the active site in the closed conformation, with red dotted lines depicting a plausible site for recognizing the terminal amine of meso-DAP³.

BIOLOGICAL
CRYSTALLOGRAPHY

ISSN: 1399-0047

Volume 69| Part 3| February 2013| Pages 420-431

doi:10.1107/S0907444912048998

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