4Z7A

Structural and biochemical characterization of a non-functionally redundant M. tuberculosis (3,3) L,D-Transpeptidase, LdtMt5.

Summary for 4Z7A

• Entry DOI: 10.2210/pdb4z7a/pdb
• Related: 3TUR 3TX4 3U1P 3U1Q 3VAE
• Descriptor: Mycobacterium tuberculosis (3,3)L,D-Transpeptidase type 5, PHOSPHATE ION, DI(HYDROXYETHYL)ETHER, ... (6 entities in total)
• Functional Keywords: peptidoglycan, cell wall biosynthesis, carbapenems, nitrocefin, enzyme kinetics, enzyme structure, antibiotics, cell wall, transferase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25177 / H37Ra)
• Total number of polymer chains: 1
• Total formula weight: 48327.83

Authors

Basta, L.,Ghosh, A.,Pan, Y.,Jakoncic, J.,Lloyd, E.,Townsend, G.,Lamichhane, G.,Bianchet, M.A. (deposition date: 2015-04-06, release date: 2015-09-02, Last modification date: 2023-09-27)

Primary citation

Brammer Basta, L.A.,Ghosh, A.,Pan, Y.,Jakoncic, J.,Lloyd, E.P.,Townsend, C.A.,Lamichhane, G.,Bianchet, M.A.
Loss of a Functionally and Structurally Distinct ld-Transpeptidase, LdtMt5, Compromises Cell Wall Integrity in Mycobacterium tuberculosis.
J.Biol.Chem., 290:25670-25685, 2015

PubMed Abstract: The final step of peptidoglycan (PG) biosynthesis in bacteria involves cross-linking of peptide side chains. This step in Mycobacterium tuberculosis is catalyzed by ld- and dd-transpeptidases that generate 3→3 and 4→3 transpeptide linkages, respectively. M. tuberculosis PG is predominantly 3→3 cross-linked, and LdtMt2 is the dominant ld-transpeptidase. There are four additional sequence paralogs of LdtMt2 encoded by the genome of this pathogen, and the reason for this apparent redundancy is unknown. Here, we studied one of the paralogs, LdtMt5, and found it to be structurally and functionally distinct. The structures of apo-LdtMt5 and its meropenem adduct presented here demonstrate that, despite overall architectural similarity to LdtMt2, the LdtMt5 active site has marked differences. The presence of a structurally divergent catalytic site and a proline-rich C-terminal subdomain suggest that this protein may have a distinct role in PG metabolism, perhaps involving other cell wall-anchored proteins. Furthermore, M. tuberculosis lacking a functional copy of LdtMt5 displayed aberrant growth and was more susceptible to killing by crystal violet, osmotic shock, and select carbapenem antibiotics. Therefore, we conclude that LdtMt5 is not a functionally redundant ld-transpeptidase, but rather it serves a unique and important role in maintaining the integrity of the M. tuberculosis cell wall.

PubMed: 26304120
DOI: 10.1074/jbc.M115.660753

Experimental method

X-RAY DIFFRACTION (1.98 Å)