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Updated: May 8, 2026
X-Ray Crystallography to Study the Oligomeric State Transition of the Thermotoga maritima M42 Aminopeptidase TmPep1050
Published on: May 13, 2020
Structures of free and inhibited forms of the L,D-transpeptidase LdtMt1 from Mycobacterium tuberculosis
Stefania Correale1, Alessia Ruggiero, Rosanna Capparelli
1Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, 80134 Napoli, Italy.
Abstract:
The modelling of peptidoglycan is responsible for key cellular processes in Mycobacterium tuberculosis such as cell growth, division and resuscitation from dormancy. The structure of M. tuberculosis peptidoglycan is atypical since it contains a majority of 3,3 cross-links synthesized by L,D-transpeptidases that replace the 4,3 cross-links formed by the D,D-transpeptidase activity of classical penicillin-binding proteins. Carbapenems inactivate these L,D-transpeptidases and in combination with clavulanic acid are bactericidal against extensively drug-resistant M. tuberculosis. Here, crystal structures of the L,D-transpeptidase LdtMt1 from M. tuberculosis in a ligand-free form and in complex with the carbapenem imipenem are reported. Elucidation of the structural features of LdtMt1 unveils analogies and differences between the two key transpeptidases of M. tuberculosis: LdtMt1 and LdtMt2. In addition, the structure of imipenem-inactivated LdtMt1 provides a detailed structural view of the interactions between a carbapenem drug and LdtMt1. By providing the key interactions in the binding of carbapenem to LdtMt1, this work will facilitate structure-guided discovery of L,D-transpeptidase inhibitors as novel antitubercular agents against drug-resistant M. tuberculosis.
Insights
Structural insights into Mycobacterium tuberculosis L,D-transpeptidase LdtMt1 reveal how carbapenem drugs like imipenem bind. This understanding aids in developing new drugs against drug-resistant tuberculosis.
Area of Science:
- Structural biology
- Microbiology
- Drug discovery
Background:
- Peptidoglycan synthesis is crucial for Mycobacterium tuberculosis survival, with L,D-transpeptidases forming atypical cross-links.
- These L,D-transpeptidases are targets for carbapenem antibiotics, which are effective against extensively drug-resistant tuberculosis.
Purpose of the Study:
- To determine the crystal structures of L,D-transpeptidase LdtMt1 from M. tuberculosis.
- To elucidate the binding interactions between LdtMt1 and the carbapenem imipenem.
Main Methods:
- X-ray crystallography was used to obtain structures of LdtMt1 in ligand-free and imipenem-bound states.
- Comparative structural analysis of LdtMt1 and LdtMt2.
Main Results:
- Crystal structures of LdtMt1 (ligand-free and imipenem-complexed) were determined.
- Detailed interactions between imipenem and LdtMt1 were visualized, showing drug inactivation mechanism.
- Structural similarities and differences between LdtMt1 and LdtMt2 were identified.
Conclusions:
- The determined structures provide a basis for understanding carbapenem activity against M. tuberculosis.
- This work facilitates structure-guided design of novel L,D-transpeptidase inhibitors for tuberculosis treatment.
