Structures of free and inhibited forms of the L,D-transpeptidase LdtMt1 from Mycobacterium tuberculosis
Structures of free and inhibited forms of the L,D-transpeptidase LdtMt1 from Mycobacterium tuberculosis
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DOI：
10.1107/s0907444913013085
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发表时间：
2013-09-01
期刊：
影响因子：
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通讯作者：
Berisio, Rita
中科院分区：
文献类型：
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作者：
Correale, Stefania;Ruggiero, Alessia;Berisio, Rita
肽聚糖的建模负责结核分枝杆菌的关键细胞过程，如细胞生长、分裂和从休眠中复苏。结核分枝杆菌肽聚糖的结构是非典型的，因为它含有大部分由L，D-转肽酶合成的3,3个交联，取代了经典青霉素结合蛋白由D，D-转肽酶活性形成的4,3个交联。碳青霉烯类使这些L、d转肽酶失活，并与克拉维酸结合，对广泛耐药的结核分枝杆菌具有杀菌作用。本文报道了无配体形式的结核分枝杆菌L， d-转肽酶Ldt（Mt1）的晶体结构，并与碳青霉烯类亚胺培南配合。阐明Ldt（Mt1）的结构特征揭示了结核分枝杆菌的两个关键转肽酶：Ldt（Mt1）和Ldt（Mt2）之间的相似性和差异。此外，亚胺培南活化的Ldt（Mt1）的结构提供了碳青霉烯类药物与Ldt（Mt1）相互作用的详细结构视图。通过提供碳青霉烯烯与Ldt（Mt1）结合的关键相互作用，这项工作将有助于在结构指导下发现L， d -转肽酶抑制剂作为抗耐药结核分枝杆菌的新型抗结核药物。
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 Ldt(Mt1) from M. tuberculosis in a ligand-free form and in complex with the carbapenem imipenem are reported. Elucidation of the structural features of Ldt(Mt1) unveils analogies and differences between the two key transpeptidases of M. tuberculosis: Ldt(Mt1) and Ldt(Mt2). In addition, the structure of imipenemin-activated Ldt(Mt1) provides a detailed structural view of the interactions between a carbapenem drug and Ldt(Mt1). By providing the key interactions in the binding of carbapenem to Ldt(Mt1), this work will facilitate structure-guided discovery of L,D-transpeptidase inhibitors as novel antitubercular agents against drug-resistant M. tuberculosis.