7f8p | pdb_00007f8p
Crystal structure of the Mycobacterium tuberculosis L,D-transpeptidase-2 (LdtMt2) with new carbapenem drug T203
Structural highlights
FunctionLDT2_MYCTU Generates 3->3 cross-links in peptidoglycan, catalyzing the cleavage of the mDap(3)-D-Ala(4) bond of a tetrapeptide donor stem and the formation of a bond between the carbonyl of mDap(3) of the donor stem and the side chain of mDap(3) of the acceptor stem. Is specific for donor substrates containing a stem tetrapeptide since it cannot use pentapeptide stems.[1] Publication Abstract from PubMedL,D-transpeptidase function predominates in atypical 3 --> 3 transpeptide networking of peptidoglycan (PG) layer in Mycobacterium tuberculosis. Prior studies of L,D-transpeptidases have identified only the catalytic site that binds to peptide moiety of the PG substrate or beta-lactam antibiotics. This insight was leveraged to develop mechanism of its activity and inhibition by beta-lactams. Here, we report identification of an allosteric site at a distance of 21 A from the catalytic site that binds the sugar moiety of PG substrates (hereafter referred to as the S-pocket). This site also binds a second beta-lactam molecule and influences binding at the catalytic site. We provide evidence that two beta-lactam molecules bind co-operatively to this enzyme, one non-covalently at the S-pocket and one covalently at the catalytic site. This dual beta-lactam-binding phenomenon is previously unknown and is an observation that may offer novel approaches for the structure-based design of new drugs against M. tuberculosis. Allosteric cooperation in beta-lactam binding to a non-classical transpeptidase.,Ahmad N, Dugad S, Chauhan V, Ahmed S, Sharma K, Kachhap S, Zaidi R, Bishai WR, Lamichhane G, Kumar P Elife. 2022 Apr 27;11. pii: 73055. doi: 10.7554/eLife.73055. PMID:35475970[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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