Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 13, Pages 3350-3355Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1710741115
Keywords
kinase; polyphosphate; enzyme structure; kinetics
Categories
Funding
- US Defense Threat Reduction Agency [HDTRA1-11-1-0007]
- Defence Science and Technology Laboratory [DSTLX1000097311]
- Engineering and Physical Sciences Research Council [EP/M507623/1]
- Human Frontiers of Science Program Grant [RGP0025/2016]
- Deutsche Forschungsgemeinschaft [RTG1976]
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Inorganic polyphosphate is a ubiquitous, linear biopolymer built of up to thousands of phosphate residues that are linked by energy-rich phosphoanhydride bonds. Polyphosphate kinases of the family 2 (PPK2) use polyphosphate to catalyze the reversible phosphorylation of nucleotide phosphates and are highly relevant as targets for new pharmaceutical compounds and as biocatalysts for cofactor regeneration. PPK2s can be classified based on their preference for nucleoside mono-or diphosphates or both. The detailedmechanism of PPK2s and the molecular basis for their substrate preference is unclear, which is mainly due to the lack of high-resolution structures with substrates or substrate analogs. Here, we report the structural analysis and comparison of a class I PPK2 (ADP-phosphorylating) and a class III PPK2 (AMP- and ADP-phosphorylating), both complexed with polyphosphate and/or nucleotide substrates. Together with complementary biochemical analyses, these define the molecular basis of nucleotide specificity and are consistent with a Mg2+ catalyzed in-line phosphoryl transfer mechanism. This mechanistic insight will guide the development of PPK2 inhibitors as potential antibacterials or genetically modified PPK2s that phosphorylate alternative substrates.
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