The crystal structure of mammalian inositol 1,3,4,5,6-pentakisphosphate 2-kinase reveals a new zinc-binding site and key features for protein function

J Biol Chem. 2017 Jun 23;292(25):10534-10548. doi: 10.1074/jbc.M117.780395. Epub 2017 Apr 27.


Inositol 1,3,4,5,6-pentakisphosphate 2-kinases (IP5 2-Ks) are part of a family of enzymes in charge of synthesizing inositol hexakisphosphate (IP6) in eukaryotic cells. This protein and its product IP6 present many roles in cells, participating in mRNA export, embryonic development, and apoptosis. We reported previously that the full-length IP5 2-K from Arabidopsis thaliana is a zinc metallo-enzyme, including two separated lobes (the N- and C-lobes). We have also shown conformational changes in IP5 2-K and have identified the residues involved in substrate recognition and catalysis. However, the specific features of mammalian IP5 2-Ks remain unknown. To this end, we report here the first structure for a murine IP5 2-K in complex with ATP/IP5 or IP6 Our structural findings indicated that the general folding in N- and C-lobes is conserved with A. thaliana IP5 2-K. A helical scaffold in the C-lobe constitutes the inositol phosphate-binding site, which, along with the participation of the N-lobe, endows high specificity to this protein. However, we also noted large structural differences between the orthologues from these two eukaryotic kingdoms. These differences include a novel zinc-binding site and regions unique to the mammalian IP5 2-K, as an unexpected basic patch on the protein surface. In conclusion, our findings have uncovered distinct features of a mammalian IP5 2-K and set the stage for investigations into protein-protein or protein-RNA interactions important for IP5 2-K function and activity.

Keywords: IP5 2-kinase; crystal structure; enzyme mutation; inositol hexakisphosphate; inositol phosphate; structure-function; zinc.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry*
  • Animals
  • Arabidopsis / enzymology
  • Arabidopsis Proteins / chemistry
  • Binding Sites
  • Crystallography, X-Ray
  • Inositol Phosphates / chemistry*
  • Mice
  • Phosphotransferases (Phosphate Group Acceptor) / chemistry*
  • Structure-Activity Relationship


  • Arabidopsis Proteins
  • Inositol Phosphates
  • Adenosine Triphosphate
  • Phosphotransferases (Phosphate Group Acceptor)
  • inositol hexakisphosphate kinase

Associated data

  • PDB/5MWL
  • PDB/5MWM
  • PDB/5MW8
  • PDB/2xan
  • PDB/2XAN