4GSR

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

Summary for 4GSR

• Entry DOI: 10.2210/pdb4gsr/pdb
• Related: 4GSQ 4GSU
• Descriptor: Probable conserved lipoprotein LPPS, 2-(ETHYLMERCURI-THIO)-BENZOIC ACID, GLYCEROL, ... (4 entities in total)
• Functional Keywords: l, d-transpeptidase, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 1
• Total formula weight: 31847.71

Authors

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. (deposition date: 2012-08-28, release date: 2013-02-27, Last modification date: 2024-03-20)

Primary citation

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.
Structural basis for the inhibition of Mycobacterium tuberculosis L,D-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains
Acta Crystallogr.,Sect.D, 69:420-431, 2013

PubMed 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.

PubMed: 23519417
DOI: 10.1107/S0907444912048998

Experimental method

X-RAY DIFFRACTION (1.79 Å)