Acta Crystallographica Section D

Biological Crystallography

Volume 69, Part 3 (March 2013)

research papers

Acta Cryst. (2013). D69, 420-431    [ doi:10.1107/S0907444912048998 ]

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

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

Abstract: Difficulty in the treatment of tuberculosis and growing drug resistance in Mycobacterium tuberculosis (Mtb) are a global health issue. Carbapenems inactivate L,D-transpeptidases; meropenem, when administered with clavulanate, showed in vivo activity against extensively drug-resistant Mtb strains. LdtMt2 (Rv2518c), one of two functional L,D-transpeptidases in Mtb, is predominantly expressed over LdtMt1 (Rv0116c). Here, the crystal structure of N-terminally truncated LdtMt2 (residues Leu131-Ala408) is reported in both ligand-free and meropenem-bound forms. The structure of meropenem-inhibited LdtMt2 provides a detailed structural view of the interactions between a carbapenem drug and Mtb L,D-transpeptidase. The structures revealed that the catalytic L,D-­transpeptidase domain of LdtMt2 is preceded by a bacterial immunogloblin-like Big_5 domain and is followed by an extended C-terminal tail that interacts with both domains. Furthermore, it is shown using mass analyses that meropenem acts as a suicide inhibitor of LdtMt2. Upon acylation of the catalytic Cys354 by meropenem, the `active-site lid' undergoes a large conformational change to partially cover the active site so that the bound meropenem is accessible to the bulk solvent via three narrow paths. This work will facilitate structure-guided discovery of L,D-transpeptidase inhibitors as novel antituberculosis drugs against drug-resistant Mtb.

PDB references: 4gsq, 4gsr and 4gsu

Keywords: Rv2518c; Mt2594; LdtMt2; L,D-transpeptidases; Mycobacterium tuberculosis; meropenem; carbapenem; peptidoglycans; antituberculosis drug discovery.

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[ doi:10.1107/S0907444912048998/be5223sup1.pdf ]
Supplementary figures and tables.


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