Journal
SCIENTIFIC REPORTS
Volume 5, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/srep08026
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Funding
- Fundacao para a Ciencia e a Tecnologia (FCT)
- EU-FEDER funding through Programa Operacional Regional do Norte (ON.2 - O Novo Norte) under Quadro de Referencia Estrategico Nacional - QREN [NORTE-07-0124-FEDER-000002]
- EU-FEDER funding through Operational Competitiveness Programme - COMPETE [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], FCOMP-01-0124-FEDER-037276 [PEst-C/SAU/LA0001/2013-2014]]
- [SFRH/BD/74845/2010]
- [SFRH/BPD/79531/2011]
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/79531/2011] Funding Source: FCT
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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 angstrom 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.
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