title: Novel inositol phospholipid headgroup surrogate crystallized in the pleckstrin homology domain of protein kinase Balpha.
abstract: Protein kinase B (PKB/Akt) plays a key role in cell signaling. The PH domain of PKB binds phosphatidylinositol 3,4,5-trisphosphate translocating PKB to the plasma membrane for activation by 3-phosphoinositide-dependent protein kinase 1. The crystal structure of the headgroup inositol 1,3,4,5-tetrakisphosphate Ins(1,3,4,5)P4-PKB complex facilitates in silico ligand design. The novel achiral analogue benzene 1,2,3,4-tetrakisphosphate (Bz(1,2,3,4)P4) possesses phosphate regiochemistry different from that of Ins(1,3,4,5)P4 and surprisingly binds with similar affinity as the natural headgroup. Bz(1,2,3,4)P4 co-crystallizes with the PKBalpha PH domain in a fashion also predictable in silico. The 2-phosphate of Bz(1,2,3,4)P4 does not interact with any residue, and the D5-phosphate of Ins(1,3,4,5)P4 is not mimicked by Bz(1,2,3,4)P4. Bz(1,2,3,4)P4 is an example of a simple inositol phosphate surrogate crystallized in a protein, and this approach could be applied to design modulators of inositol polyphosphate binding proteins.
authors: Stephen J
authors: SJ
authors: Mills
authors: David
authors: D
authors: Komander
authors: Melanie N
authors: MN
authors: Trusselle
authors: Stephen T
authors: ST
authors: Safrany
authors: Daan M F
authors: DM
authors: van Aalten
authors: Barry V L
authors: BV
authors: Potter
mesh_terms: D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D010755:Organophosphates / Q000737:chemistry / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D010755:Organophosphates; D018129:Phosphatidylinositol Phosphates; C519563:benzene 1,2,3,4-tetrakisphosphate; C060974:phosphatidylinositol 3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt