Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/109319
Title: Structure of mycobacterial maltokinase, the missing link in the essential GlgE-pathway
Authors: Fraga, Joana 
Maranha, Ana 
Mendes, Vítor 
Pereira, Pedro José Barbosa
Empadinhas, Nuno 
Macedo-Ribeiro, Sandra 
Issue Date: 26-Jan-2015
Publisher: Springer Nature
Project: PTDC/BIA-PRO/110523/2009 
PTDC/BIA-BCM/112459/2009 
PTDC/BIA-MIC/2779/2012 
PEst-C/SAU/LA0001/2013 
SFRH/BD/74845/2010 
SFRH/BPD/79531/2011 
Serial title, monograph or event: Scientific Reports
Volume: 5
Issue: 1
Abstract: A novel four-step pathway identified recently in mycobacteria channels trehalose to glycogen synthesis and is also likely involved in the biosynthesis of two other crucial polymers: intracellular methylglucose lipopolysaccharides and exposed capsular glucan. The structures of three of the intervening enzymes - GlgB, GlgE, and TreS - were recently reported, providing the first templates for rational drug design. Here we describe the structural characterization of the fourth enzyme of the pathway, mycobacterial maltokinase (Mak), uncovering a eukaryotic-like kinase (ELK) fold, similar to methylthioribose kinases and aminoglycoside phosphotransferases. The 1.15 Å structure of Mak in complex with a non-hydrolysable ATP analog reveals subtle structural rearrangements upon nucleotide binding in the cleft between the N- and the C-terminal lobes. Remarkably, this new family of ELKs has a novel N-terminal domain topologically resembling the cystatin family of protease inhibitors. By interfacing with and restraining the mobility of the phosphate-binding region of the N-terminal lobe, Mak's unusual N-terminal domain might regulate its phosphotransfer activity and represents the most likely anchoring point for TreS, the upstream enzyme in the pathway. By completing the gallery of atomic-detail models of an essential pathway, this structure opens new avenues for the rational design of alternative anti-tubercular compounds.
URI: https://hdl.handle.net/10316/109319
ISSN: 2045-2322
DOI: 10.1038/srep08026
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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