Novel inositol phospholipid headgroup surrogate crystallized in the pleckstrin homology domain of protein kinase Bα

TY - JOUR

T1 - Novel inositol phospholipid headgroup surrogate crystallized in the pleckstrin homology domain of protein kinase Bα

AU - Mills, Stephen J.

AU - Komander, David

AU - Trusselle, Melanie N.

AU - Safrany, Stephen T.

AU - van Aalten, Daan M. F.

AU - Potter, Barry V. L.

N1 - Copyright 2008 Elsevier B.V., All rights reserved.

PY - 2007/4/1

Y1 - 2007/4/1

N2 - 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)P 4-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)P 4 and surprisingly binds with similar affinity as the natural headgroup. Bz(1,2,3,4)P 4 co-crystallizes with the PKBa PH domain in a fashion also predictable in silico. The 2-phosphate of Bz(1,2,3,4)P 4 does not interact with any residue, and the D5-phosphate of Ins(1,3,4,5)P 4 is not mimicked by Bz(1,2,3,4)P 4. Bz(1,2,3,4)P 4 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.

AB - 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)P 4-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)P 4 and surprisingly binds with similar affinity as the natural headgroup. Bz(1,2,3,4)P 4 co-crystallizes with the PKBa PH domain in a fashion also predictable in silico. The 2-phosphate of Bz(1,2,3,4)P 4 does not interact with any residue, and the D5-phosphate of Ins(1,3,4,5)P 4 is not mimicked by Bz(1,2,3,4)P 4. Bz(1,2,3,4)P 4 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.

UR - https://www.scopus.com/pages/publications/34248549518

U2 - 10.1021/cb700019r

DO - 10.1021/cb700019r

M3 - Article

AN - SCOPUS:34248549518

SN - 1554-8929

VL - 2

SP - 242

EP - 246

JO - ACS Chemical Biology

JF - ACS Chemical Biology

IS - 4

ER -