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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\u2005\u00c5 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.<\/jats:p>","DOI":"10.1038\/srep08026","type":"journal-article","created":{"date-parts":[[2015,1,26]],"date-time":"2015-01-26T10:03:08Z","timestamp":1422266588000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":743,"title":["Structure of mycobacterial maltokinase, the missing link in the essential GlgE-pathway"],"prefix":"10.1038","volume":"5","author":[{"given":"Joana","family":"Fraga","sequence":"first","affiliation":[]},{"given":"Ana","family":"Maranha","sequence":"additional","affiliation":[]},{"given":"Vitor","family":"Mendes","sequence":"additional","affiliation":[]},{"given":"Pedro Jos\u00e9 Barbosa","family":"Pereira","sequence":"additional","affiliation":[]},{"given":"Nuno","family":"Empadinhas","sequence":"additional","affiliation":[]},{"given":"Sandra","family":"Macedo-Ribeiro","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2015,1,26]]},"reference":[{"key":"BFsrep08026_CR1","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1111\/j.1365-2958.2008.06445.x","volume":"70","author":"T Sambou","year":"2008","unstructured":"Sambou, T. et al. Capsular glucan and intracellular glycogen of Mycobacterium tuberculosis: biosynthesis and impact on the persistence in mice. Mol Microbiol 70, 762\u2013774, 10.1111\/j.1365-2958.2008.06445.x (2008).","journal-title":"Mol Microbiol"},{"key":"BFsrep08026_CR2","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1099\/mic.0.044263-0","volume":"157","author":"G Chandra","year":"2011","unstructured":"Chandra, G., Chater, K. F. & Bornemann, S. Unexpected and widespread connections between bacterial glycogen and trehalose metabolism. Microbiology 157, 1565\u20131572, 10.1099\/mic.0.044263-0 (2011).","journal-title":"Microbiology"},{"key":"BFsrep08026_CR3","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nchembio.340","volume":"6","author":"R Kalscheuer","year":"2010","unstructured":"Kalscheuer, R. et al. Self-poisoning of Mycobacterium tuberculosis by targeting GlgE in an alpha-glucan pathway. 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