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Allosteric cooperation in β-lactam binding to a non-classical transpeptidase.
| Content Provider | Europe PMC |
|---|---|
| Author | Ahmad, Nazia Dugad, Sanmati Chauhan, Varsha Ahmed, Shubbir Sharma, Kunal Kachhap, Sangita Zaidi, Rana Bishai, William R Lamichhane, Gyanu Kumar, Pankaj |
| Editor | Dassama, Laura Boudker, Olga |
| Copyright Year | 2022 |
| Abstract | 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. |
| Journal | eLife |
| Volume Number | 11 |
| PubMed Central reference number | PMC9094749 |
| PubMed reference number | 35475970 |
| e-ISSN | 2050084X |
| DOI | 10.7554/elife.73055 |
| Language | English |
| Publisher | eLife Sciences Publications, Ltd |
| Publisher Date | 2022-04-27 |
| Access Restriction | Open |
| Rights License | This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. © 2022, Ahmad et al |
| Subject Keyword | Mycobacterium tuberculosis β-lactam peptidoglycan L,D-transpeptidase allostery |
| Content Type | Text |
| Resource Type | Article |
| Subject | Immunology and Microbiology Neuroscience Medicine Biochemistry, Genetics and Molecular Biology |
