Structural and binding properties of the PASTA domain of PonA2, a key penicillin binding protein from Mycobacterium tuberculosis

PonA2 is one of the two class A Penicillin binding proteins of Mycobacterium tuberculosis , the etiologic agent of tuberculosis. It plays a c omplex role in mycobacterial physiology and is spotted as a promising target for inhibitors. PonA2 is involved in adaptation of M. tuberculosis to dormancy, an ability which has been attributed to the presence in its sequence of a C6terminal PASTA domain. Since PASTA modules are ty pically considered as ?? 6lactam antibiotic binding domains, we determined the solution structu re of the PASTA domain from PonA2 and analysed its binding properties versus a plethora of potential binders, including the ??6l actam antibiotics, two typical muropeptide mimics and pol ymeric peptidoglycan. We show that, despite a high structural similarity with other PASTA domains , the PASTA domain of PonA2 displays different binding properties, as it is not able to bind muropeptides, nor ??6lactams, nor polymeric peptidoglycan. These results indicate that the role of PASTA domains cannot be generalized, as their specific binding properties strongly depend o n surface residues, which are widely variable.