Allosteric cooperation in ß-lactam binding to a non-classical transpeptidase
- Jamia Hamdard University, India
- Johns Hopkins University, United States
- Translational Health Science and Technology Institute, India
- Polish Academy of Sciences, Poland
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 ß-lactam antibiotics. This insight was leveraged to develop mechanism of its activity and inhibition by ß-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 ß-lactam molecule and influences binding at the catalytic site. We provide evidence that two ß-lactam molecules bind co-operatively to this enzyme, one non-covalently at the S-pocket and one covalently at the catalytic site. This dual ß-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./em>.
Data availability
Diffraction data have been deposited in PDB under the accession code 7F71, 7F8P
Article and author information
Author details
Funding
Science and Engineering Research Board (CRG/2019/005079)
- Pankaj Kumar
National Institutes of Health (R33 AI111739)
- Gyanu Lamichhane
National Institutes of Health (R21 R01 AI155664)
- Gyanu Lamichhane
Department of Biotechnology, Ministry of Science and Technology, India (BT-RLF/Re-entry/68/2017)
- Pankaj Kumar
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Laura Dassama, Stanford University, United States
Version history
- Received: August 14, 2021
- Preprint posted: September 6, 2021 (view preprint)
- Accepted: April 26, 2022
- Accepted Manuscript published: April 27, 2022 (version 1)
- Accepted Manuscript updated: April 29, 2022 (version 2)
- Version of Record published: May 11, 2022 (version 3)
Copyright
© 2022, Ahmad et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Allosteric cooperation in ß-lactam binding to a non-classical transpeptidase
eLife 11:e73055.
https://doi.org/10.7554/eLife.73055
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