Structure of inositol polyphosphate kinases. a) Inositol 1,4,5-trisphosphate 3-kinase (I3P3K) (PDB|1w2c ) adopts a lipid kinase/protein kinase-like fold. Common core of lipid kinases, eukaryotic protein kinases, and I3P3K is shown in blue (α-helices) and yellow (β-strands); additional elements are grey. Residue 1 (Lys209) interacts with the nucleotide's phosphate tail, residue 2 (Glu215) stabilizes the orientation of residue 1, residue 3 (Asp262) binds the sugar group of ATP, residue 4 (Lys264) likely interacts with the γ-phosphate during transfer, and residues 5 (Ser399) and 6 (Asp416) are both likely involved in coordinating two Mg2+ cations. Mn2+ is shown as a green ball and inositol 1,4,5-trisphosphate is shown in purple. b) Multiple sequence alignment of I3P3K (gi|10176869, PDB|1w2c, PDB|1tzd) and I5P2K (gi|6320521) with two related kinase families: lipid kinase representative PIPK (PDB|1bo1 ; Family 1b) and protein kinase representative twitchin kinase (PDB|1koa ; Family 1a). Italics denote α-helical regions for which the register of structure-based alignment cannot be obtained unequivocally due to significant structural divergence. Critical active site residues are indicated by white bold text highlighted in black/magenta, and are numbered the same as in panel (a). Magenta highlighting indicates residues that perform equivalent roles and are found in equivalent spatial locations, but do not align closely in sequence between the lipid kinase and protein kinase families. In this and other multiple alignments, sequences are labelled according to the NCBI gene identification (gi) number or PDB code and an abbreviation of the species name. Abbreviations in this alignment are as follows: Ag Anopheles gambiae, Am Apis mellifera, At Arabidopsis thaliana, Ce Caenorhabditis elegans, Dh Debaryomyces hansenii, Dm Drosophila melanogaster, Gg Gallus gallus, Gz Gibberella zeae, Hs Homo sapiens, Mg Mytilus galloprovincialis, Mm Mus musculus, Rn Rattus norvegicus, Sc Saccharomyces cerevisiae. First and last residue numbers are indicated before and after each sequence. Numbers of excluded residues are specified in square brackets. Residue conservation is denoted with the following scheme: mostly hydrophobic positions, highlighted yellow; mostly charged/polar positions, highlighted grey; small residues, red bold text. Locations of predicted (gi|6320521, gi|10176869) and observed (PDB|1w2c_A, PDB|1tzd_B, PDB|1bo1_A, PDB|1koa) secondary structure elements (E, β-strand; H, α-helix) are marked above the sequences (with the exception of gi|10176869 which is shown below the sequence) in italics and normal font, respectively.