Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains

Mol Cell. 2000 Aug;6(2):385-94. doi: 10.1016/s1097-2765(00)00038-1.


Lipid second messengers generated by phosphoinositide (PI) 3-kinases regulate diverse cellular functions through interaction with pleckstrin homology (PH) domains in modular signaling proteins. The PH domain of Grp1, a PI 3-kinase-activated exchange factor for Arf GTPases, selectively binds phosphatidylinositol 3,4,5-trisphosphate with high affinity. We have determined the structure of the Grp1 PH domain in the unliganded form and bound to inositol 1,3,4,5-tetraphosphate. A novel mode of phosphoinositide recognition involving a 20-residue insertion within the beta6/beta7 loop explains the unusually high specificity of the Grp1 PH domain and the promiscuous 3-phosphoinositide binding typical of several PH domains including that of protein kinase B. When compared to other PH domains, general determinants of 3-phosphoinositide recognition and specificity can be deduced.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Binding Sites
  • Conserved Sequence
  • Crystallography, X-Ray
  • Inositol Phosphates / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphatidylinositols / metabolism*
  • Protein Conformation
  • Protein Structure, Secondary
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • src Homology Domains


  • Inositol Phosphates
  • Phosphatidylinositols
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • phosphatidylinositol receptors
  • Phosphatidylinositol 3-Kinases

Associated data

  • PDB/1FGY
  • PDB/1FGZ