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bioRxiv · 10.1101/2021.09.06.459080

Allosteric cooperation in β-lactam binding to a non-classical transpeptidase

Ahmad, N.·Kachhap, S.·Chauhan, V.·Juneja, P.·Sharma, K.·Bullen, C. K.·Borowski, T.·Bishai, W. R.·Lamichhane, G.·Kumar, P.
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Abstract

Mycobacterium tuberculosis peptidoglycan (PG) is atypical as its synthesis involves a new enzyme class, L,D-transpeptidases. 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-site 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 {beta}-lactam antibiotics for M. tuberculosis.

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Ahmad, N., Kachhap, S., Chauhan, V., Juneja, P., Sharma, K., Bullen, C. K., Borowski, T., Bishai, W. R., Lamichhane, G., Kumar, P.. 2021-09-06. Allosteric cooperation in β-lactam binding to a non-classical transpeptidase. https://doi.org/10.1101/2021.09.06.459080

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