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Structural and functional characterization of malate synthase G from opportunistic pathogen Pseudomonas aeruginosa

DOI: 10.1021/acs.biochem.7b00852 DOI Help

Authors: Alyssa C. Mcvey (University of Cambridge) , Prasanthi Medarametla (University of Eastern Finland) , Xavier Chee (University of Cambridge) , Sean Bartlett (University of Cambridge) , Antti Poso (University of Eastern Finland; University Hospital Tübingen) , David R. Spring (University of Cambridge) , Taufiq Rahman (University of Cambridge) , Martin Welch (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemistry

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 14043

Open Access Open Access

Abstract: Pseudomonas aeruginosa is an opportunistic human pathogen recognized as a critical threat by the World Health Organization because of the dwindling number of effective therapies available to treat infections. Over the past decade, it has become apparent that the glyoxylate shunt plays a vital role in sustaining P. aeruginosa during infection scenarios. The glyoxylate shunt comprises two enzymes: isocitrate lyase and malate synthase isoform G. Inactivation of these enzymes has been reported to abolish the ability of P. aeruginosa to establish infection in a mammalian model system, yet we still lack the structural information to support drug design efforts. In this work, we describe the first X-ray crystal structure of P. aeruginosa malate synthase G in the apo form at 1.62 Å resolution. The enzyme is a monomer composed of four domains and is highly conserved with homologues found in other clinically relevant microorganisms. It is also dependent on Mg2+ for catalysis. Metal ion binding led to a change in the intrinsic fluorescence of the protein, allowing us to quantitate its affinity for Mg2+. We also identified putative drug binding sites in malate synthase G using computational analysis and, because of the high resolution of the experimental data, were further able to characterize its hydration properties. Our data reveal two promising binding pockets in malate synthase G that may be exploited for drug design.

Journal Keywords: Peptides and proteins; Monomers; Crystal structure; Molecules; Screening assays

Diamond Keywords: Bacteria

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

Instruments: I03-Macromolecular Crystallography

Added On: 09/10/2017 09:13


Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)