Acta Cryst. (2013). D69, 420-431 [ doi:10.1107/S0907444912048998 ]
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.
Portable Document Format (PDF) file (976.4 kbytes)
To open or display or play some files, you may need to set your browser up to use the appropriate software. See the full list of file types for an explanation of the different file types and their related mime types and, where available links to sites from where the appropriate software may be obtained.
The download button will force most browsers to prompt for a file name to store the data on your hard disk.
Where possible, images are represented by thumbnails.