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7f71

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Crystal structure of the Mycobacterium tuberculosis L,D-transpeptidase-2 (LdtMt2) with peptidoglycan sugar moiety and glutamate

Structural highlights

7f71 is a 2 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.58Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LDT2_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 PubMed

L,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

↑ Cordillot M, Dubee V, Triboulet S, Dubost L, Marie A, Hugonnet JE, Arthur M, Mainardi JL. In vitro cross-linking of Mycobacterium tuberculosis peptidoglycan by L,D-transpeptidases and inactivation of these enzymes by carbapenems. Antimicrob Agents Chemother. 2013 Dec;57(12):5940-5. doi: 10.1128/AAC.01663-13., Epub 2013 Sep 16. PMID:24041897 doi:http://dx.doi.org/10.1128/AAC.01663-13
↑ Ahmad N, Dugad S, Chauhan V, Ahmed S, Sharma K, Kachhap S, Zaidi R, Bishai WR, Lamichhane G, Kumar P. Allosteric cooperation in beta-lactam binding to a non-classical transpeptidase. Elife. 2022 Apr 27;11. pii: 73055. doi: 10.7554/eLife.73055. PMID:35475970 doi:http://dx.doi.org/10.7554/eLife.73055