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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: | This work was funded by national funds through Fundaça˜o para a Cieˆncia e a Tecnologia (FCT) and by EU-FEDER funding through Programa Operacional Regional do Norte (ON.2 - O Novo Quadro de Refereˆncia Estrate´gico Nacional – QREN (grant NORTE-07-0124-FEDER-000002 - Host-Pathogen Interactions), and through the Operational Competitiveness Programme – COMPETE (grants FCOMP-01-0124-FEDER-014321 [PTDC/BIA-PRO/110523/2009], FCOMP-01-0124-FEDER-014187 [PTDC/BIA-BCM/112459/2009], FCOMP-01-0124-FEDER-028359 [PTDC/BIA-MIC/2779/2012], and FCOMP-01-0124-FEDER-037276 [PEst-C/SAU/LA0001/2013-2014]). The financial support of FCT through fellowships SFRH/BD/74845/2010 (A.M.) and SFRH/BPD/79531/ 2011 (V.M.) is also acknowledged. | 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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