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

  1. Nazia Ahmad
  2. Sanmati Dugad
  3. Varsha Chauhan
  4. Shubbir Ahmed
  5. Kunal Sharma
  6. Sangita Kachhap
  7. Rana Zaidi
  8. William R Bishai
  9. Gyanu Lamichhane  Is a corresponding author
  10. Pankaj Kumar  Is a corresponding author
  1. Jamia Hamdard University, India
  2. Johns Hopkins University, United States
  3. Translational Health Science and Technology Institute, India
  4. 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

The following data sets were generated

Article and author information

Author details

  1. Nazia Ahmad

    Department of Biochemistry, Jamia Hamdard University, Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Sanmati Dugad

    Department of Infectious Diseases, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Varsha Chauhan

    Department of Infectious Diseases, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shubbir Ahmed

    NCR Biotech Science Cluster, Translational Health Science and Technology Institute, Faridabad, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Kunal Sharma

    Department of Biochemistry, Jamia Hamdard University, Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  6. Sangita Kachhap

    Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Niezapominajek, Poland
    Competing interests
    The authors declare that no competing interests exist.
  7. Rana Zaidi

    Department of Biochemistry, Jamia Hamdard University, Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  8. William R Bishai

    Department of Infectious Diseases, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8734-4118
  9. Gyanu Lamichhane

    Department of Infectious Diseases, Johns Hopkins University, Baltimore, United States
    For correspondence
    gyanu@jhu.edu
    Competing interests
    The authors declare that no competing interests exist.
  10. Pankaj Kumar

    Medicine, Johns Hopkins University, Baltimore, United States
    For correspondence
    pkumar10@jhmi.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9163-3273

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

  1. Laura Dassama, Stanford University, United States

Version history

  1. Received: August 14, 2021
  2. Preprint posted: September 6, 2021 (view preprint)
  3. Accepted: April 26, 2022
  4. Accepted Manuscript published: April 27, 2022 (version 1)
  5. Accepted Manuscript updated: April 29, 2022 (version 2)
  6. 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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  1. Nazia Ahmad
  2. Sanmati Dugad
  3. Varsha Chauhan
  4. Shubbir Ahmed
  5. Kunal Sharma
  6. Sangita Kachhap
  7. Rana Zaidi
  8. William R Bishai
  9. Gyanu Lamichhane
  10. Pankaj Kumar
(2022)
Allosteric cooperation in ß-lactam binding to a non-classical transpeptidase
eLife 11:e73055.
https://doi.org/10.7554/eLife.73055

Share this article

https://doi.org/10.7554/eLife.73055

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    Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown.

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    This study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR.

    Funding:

    This work was supported by the Weizmann Krenter Foundation and the Weizmann – Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.