TY - JOUR TI - Allosteric cooperation in β-lactam binding to a non-classical transpeptidase AU - Ahmad, Nazia AU - Dugad, Sanmati AU - Chauhan, Varsha AU - Ahmed, Shubbir AU - Sharma, Kunal AU - Kachhap, Sangita AU - Zaidi, Rana AU - Bishai, William R AU - Lamichhane, Gyanu AU - Kumar, Pankaj A2 - Dassama, Laura A2 - Boudker, Olga A2 - Haider, Shozeb VL - 11 PY - 2022 DA - 2022/04/27 SP - e73055 C1 - eLife 2022;11:e73055 DO - 10.7554/eLife.73055 UR - https://doi.org/10.7554/eLife.73055 AB - 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 β-lactam antibiotics. This insight was leveraged to develop mechanism of its activity and inhibition by β-lactams. Here, we report identification of an allosteric site at a distance of 21 Å 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 β-lactam molecule and influences binding at the catalytic site. We provide evidence that two β-lactam molecules bind co-operatively to this enzyme, one non-covalently at the S-pocket and one covalently at the catalytic site. This dual β-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. KW - Mycobacterium tuberculosis KW - β-lactam KW - peptidoglycan KW - L,D-transpeptidase KW - allostery JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -