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Conformational dynamics of the membrane enzyme LspA upon antibiotic and substrate binding
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Caldwell, Tracy A., Vickery, Owen N., Colburn, Jonathan David, Stansfeld, Phillip J. and Columbus, Linda (2022) Conformational dynamics of the membrane enzyme LspA upon antibiotic and substrate binding. Biophysical Journal, 121 (11). pp. 2078-2083. doi:10.1016/j.bpj.2022.04.038 ISSN 0006-3495.
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Official URL: https://doi.org/10.1016/j.bpj.2022.04.038
Abstract
Lipoprotein signal peptidase (LspA) is an aspartyl protease that cleaves the transmembrane helix signal peptide of lipoproteins as part of the lipoprotein processing pathway. Members of this pathway are excellent targets for the development of antibiotic therapeutics because they are essential in Gram-negative bacteria, are important for virulence in Gram-positive bacteria, and may not develop antibiotic resistance. Here we report the conformational dynamics of LspA in the apo state and bound to the antibiotic globomycin determined using MD simulations and EPR. The periplasmic helix fluctuates on the nanosecond timescale and samples unique conformations in the different states. In the apo state, the dominant conformation is the most closed and occludes the charged active site from the lipid bilayer. With antibiotic bound there are multiple binding modes with the dominant conformation of the periplasmic helix in a more open conformation. The different conformations observed in both bound and apo states indicate a flexible and adaptable active site, which explains how LspA accommodates and processes such a variety of substrates.
| Item Type: | Journal Article | |||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QH Natural history Q Science > QP Physiology T Technology > TP Chemical technology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Science > Chemistry > Computational and Theoretical Chemistry Centre |
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| Library of Congress Subject Headings (LCSH): | Lipoproteins, Cell membranes, Enzymes, Peptides, Antibiotics -- Biotechnology, Drug resistance in microorganisms -- Prevention | |||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Biophysical Journal | |||||||||||||||||||||||||||||||||
| Publisher: | Biophysical Society ; Elsevier | |||||||||||||||||||||||||||||||||
| ISSN: | 0006-3495 | |||||||||||||||||||||||||||||||||
| Official Date: | 7 June 2022 | |||||||||||||||||||||||||||||||||
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| Volume: | 121 | |||||||||||||||||||||||||||||||||
| Number: | 11 | |||||||||||||||||||||||||||||||||
| Page Range: | pp. 2078-2083 | |||||||||||||||||||||||||||||||||
| DOI: | 10.1016/j.bpj.2022.04.038 | |||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||||||||||||||||||||
| Publication Status: | Published | |||||||||||||||||||||||||||||||||
| Access rights to Published version: | Restricted or Subscription Access | |||||||||||||||||||||||||||||||||
| Date of first compliant deposit: | 4 May 2022 | |||||||||||||||||||||||||||||||||
| Date of first compliant Open Access: | 2 May 2023 | |||||||||||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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