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

DOI: 10.1016/j.jbc.2021.100307 DOI Help

Authors: Christopher M. Furze (University of Warwick) , Ignacio Delso (Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Universidad de Zaragoza; University of East Anglia) , Enriqueta Casal (University of East Anglia) , Collette S. Guy (University of Warwick) , Chloe Seddon (University of Warwick) , Chelsea M. Brown (University of Warwick) , Hadyn L. Parker (University of Warwick) , Anjana Radhakrishnan (University of Warwick) , Raul Pacheco-Gomez (Malvern Panalytical Ltd) , Phillip J. Stansfeld (University of Warwick) , Jesus Angulo (University of East Anglia; Universidad de Sevilla; Instituto de Investigaciones Químicas (CSIC-US)) , Alexander D. Cameron (University of Warwick) , Elizabeth Fullam (University of Warwick)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry , VOL 367

State: Published (Approved)
Published: January 2021
Diamond Proposal Number(s): 19880

Open Access Open Access

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.

Journal Keywords: Mycobacterium tuberculosis; trehalose; carbohydrate; ABC transporter; LpqY-SugABC transporter; structural biology; structure-function

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 20/01/2021 10:16


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)