title: Structures of free and inhibited forms of the L,D-transpeptidase LdtMt1 from Mycobacterium tuberculosis.
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.
authors.affiliation: Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, 80134 Napoli, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Correale
authors.forename: Alessia
authors.initials: A
authors.lastname: Ruggiero
authors.forename: Rosanna
authors.initials: R
authors.lastname: Capparelli
authors.forename: Emilia
authors.initials: E
authors.lastname: Pedone
authors.forename: Rita
authors.initials: R
authors.lastname: Berisio
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D020134:Catalytic Domain; D003460:Crystallization; D018360:Crystallography, X-Ray; D015378:Imipenem / Q000494:pharmacology / Q000627:therapeutic use; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D010458:Peptidyl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D011994:Recombinant Proteins; D015378:Imipenem; D010458:Peptidyl Transferases
keywords: cell wall; l,d-transpeptidases; peptidoglycan; tuberculosis