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Structural basis of trehalose recognition by the mycobacterial LpqY-SugABC transporter

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Furze, Christopher M., Delso, Ignacio, Casal, Enriqueta, Guy, Collette S., Seddon, Chloe, Brown, Chelsea M., Parker, Hadyn L., Radhakrishnan, Anjana, Pacheco-Gomez, Raul, Stansfeld, Phillip J., Angulo, Jesus, Cameron, Alexander D. and Fullam, Elizabeth (2021) Structural basis of trehalose recognition by the mycobacterial LpqY-SugABC transporter. Journal of Biological Chemistry, 296 . 100307. doi:10.1016/j.jbc.2021.100307

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Official URL: http://dx.doi.org/10.1016/j.jbc.2021.100307

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Abstract

The Mycobacterium tuberculosis (Mtb) LpqY-SugABC ATP-binding cassette transporter is a recycling system that imports trehalose released during remodelling of the Mtb cell-envelope. As this process is essential for the virulence of the Mtb pathogen it may represent an important target for tuberculosis drug and diagnostic development, but the transporter specificity and molecular determinants of substrate recognition are unknown. To address this, we have determined the structural and biochemical basis of how mycobacteria transport trehalose using a combination of crystallography, STD NMR, molecular dynamics, site-directed mutagenesis, biochemical/biophysical assays and the synthesis of trehalose analogues. This analysis pinpoints key residues of the LpqY substrate binding lipoprotein that dictate substrate-specific recognition and has revealed which disaccharide modifications are tolerated. These findings provide critical insights into how the essential Mtb LpqY-SugABC transporter reuses trehalose and modified analogues, and specifies a framework that can be exploited for the design of new anti-tubercular agents and/or diagnostic tools.

Item Type: Journal Article
Subjects: Q Science > QP Physiology
Q Science > QR Microbiology
T Technology > TP Chemical technology
Divisions: Faculty of Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Mycobacterium tuberculosis , Trehalose , ATP-binding cassette transporters
Journal or Publication Title: Journal of Biological Chemistry
Publisher: American Society for Biochemistry and Molecular Biology
ISSN: 0021-9258
Official Date: 1 January 2021
Dates:
DateEvent
1 January 2021Published
18 January 2021Available
15 January 2021Accepted
Date of first compliant deposit: 3 February 2021
Volume: 296
Article Number: 100307
DOI: 10.1016/j.jbc.2021.100307
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
104193/Z/14/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
104193/Z/14/ZRoyal Societyhttp://dx.doi.org/10.13039/501100000288
104193/Z/14/BWellcome Trusthttp://dx.doi.org/10.13039/100010269
104193/Z/14/BRoyal Societyhttp://dx.doi.org/10.13039/501100000288
RG120405Royal Societyhttp://dx.doi.org/10.13039/501100000288
RPG-2019-087Leverhulme Trusthttp://dx.doi.org/10.13039/501100000275
BB/M01116X/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
MR/N014294/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/M017982/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/P010660/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
UNSPECIFIEDUniversidad de Sevillahttp://dx.doi.org/10.13039/100009042
EP/R029407/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
EP/P020232/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266

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